Ariel Fernandez's Rocky Biophysics

Missing science in biomolecular design

Ariel Fernandez May Have Created a WaterMap Precursor in 2007

Contributed by Weishi L. Meng, reproduced from Science Transparency.

   Drug designers often implement molecular therapies to block malfunctioning proteins that are causing disease. They do so by creating small molecules that bind to the intended protein target when suitably delivered. The procedure has its risks as unintended targets (off-target proteins) may also be hit or impaired, especially when they are structurally similar (homologous) to the intended target. To achieve specificity and improve affinity for the intended target, practitioners in drug design often use WaterMap®, a product of the NY-based company Schrodinger. WaterMap is regarded by some as a gold standard in the field.

   What does WaterMap do? It identifies water molecules surrounding the protein target that may be easily removable as the purported drug binds to the target. Thus, a WaterMap of the target-water interface may provide the designer with valuable information to optimize a given drug lead. Since WaterMaps of homologous proteins are somewhat different, they may be used to tell apart homologs through selective molecular recognition. This much almost everyone knows…

   So, who pioneered these “WaterMaps”? One would assume Schrodinger scientists did, who else? Well, maybe they were not the first to get there. A similar method was published earlier and the Schrodinger folks may have not been aware of it. The facts are that in May and December of 2007, Ariel Fernandez and coworkers published two papers on the local lability of interfacial water and contrasted the “dewetting propensity” patterns across protein targets to design anticancer drugs with controlled drug specificity. These papers are: Fernandez et al. Cancer Research, 2007, Priority Report, and Fernández, A., et al. (2007) Journal of Clinical Investigation 117:4044-4054. The former contains what Ariel Fernandez has named “local dewetting propensities” that surely look like precursors to WaterMap and were featured in the cover of Cancer Research for the May 1, 2007 issue. In December of 2007, in Figs 1-3 in Fernández, A. et al. (2007) Journal of Clinical Investigation 117:4044-4054, you may find the first “WaterMap” analysis of two proteins that needed to be differentiated through molecular recognition.

First "WaterMap" by Ariel Fernandez, probably a precursor to WaterMap.

First “WaterMap” by Ariel Fernandez, probably a precursor to WaterMap.

CANCER RESEARCH MAY 1, 2007 COVER LEGEND: Extensive exposure to molecular targeted therapy elicits mechanisms of drug resistance, typically promoting mutations in the protein target that lower the affinity for the drug inhibitor. Thus, protein kinases, the central targets for drug-based cancer treatment, avoid functional impairment by developing adaptive mutations. Redesigning a drug to target a drug-resistant mutant kinase constitutes a therapeutic challenge. Fernández et al. approach this problem by redesigning the anticancer drug imatinib guided by local changes in interfacial de-wetting propensities of the C-Kit kinase target introduced by an imatinib-resistant mutation. The ligand is redesigned by sculpting the shifting hydration patterns of the target, quantified by the bar plot in the figure. The association with the modified ligand overcomes the mutation-driven destabilization of the induced fit, as shown in the bottom molecular displays. Consequently, the redesigned drug inhibits both mutant and wild-type kinase. The modeling effort is validated through molecular dynamics, test tube kinetic assays of downstream phosphorylation activity, high-throughput bacteriophage-display kinase screening,cellular proliferation assays, and cellular immunoblots. The inhibitor redesign reported delineates a molecular engineering paradigm to impair routes for drug resistance. Inspired by these findings, Fernández et al. envision a strategy for drug redesign that “corners” mutation-induced adaptation, so that the only recourse to avoid drug-promoted inhibition becomes a mutation that renders the target protein functionally inactive. For details, see the article by Fernández et al.on page 4028 in this issue.

   Evidently, the method introduced by Ariel Fernandez and highlighted in the figure caption above is a precursor, possibly equivalent, to WaterMap. Furthermore, it is likely that a 3-body energy contribution described in Ariel Fernandez’s books has been omitted in the standard WaterMap analysis of “counterintuitive” desolvation sites. Usual computations of the reversible work to transfer interfacial water to the bulk do not take into account that, as water is displaced by a nonpolar group upon ligand binding, nearby preformed intramolecular hydrogen bonds that were previously exposed to solvent (dehydrons) become strengthened and more stable. Thus, the nonpolar group may be designed to displace water originally hydrating a polar group only if the latter is hydrogen bonded to another polar forming a dehydron. “Wrapping preformed hydrogen bonds” in this way stabilizes the drug-target complex, thereby enhancing affinity. This is a three-body effect (nonpolar with polar pair) that Ariel Fernandez named “wrapping interaction”.

Physics at the Biomolecular Interface: Review on Ariel Fernandez’s Book by Weishi Meng

Book Review by Weishi Meng (Reproduced with permission)

Physics at the Biomolecular Interface” is the latest book by Ariel Fernandez (阿列尔·费尔南德斯), the physical chemist and mathematician who developed the center manifold thermodynamics, unraveling the physical basis for the onset of life, and discovered the dehydron (脱水元), an idea that laid the foundation for the new field of epistructural biology. The hardcover is expected by June 8, 2016. The bibliographic information is as follows:

Title: Physics at the Biomolecular Interface

Subtitle: Fundamentals for Molecular Targeted Therapy

Series: Soft and Biological Matter

Author: Ariel Fernández

Publisher: Springer International Publishing, Switzerland

Hardcover ISBN: 978-3-319-30851-7

eBook ISBN: 978-3-319-30852-4

Number of pages: 483

Ariel Fernandez Book Cover

Ariel Fernandez Book Cover

Physics at the Biomolecular Interface, the third book by Ariel Fernandez, is no bedtime reading. Conceptually intricate and highly interdisciplinary but cast in Fernandez’s beautiful supple prose, this monumental work is, without a doubt Fernandez’s opus magnum. It  provides the fundamental scientific framework and discourse to handle biological matter physics, exploring the evolutionary axis of biology from the physicist perspective. In the author’s own words:

…the biological functionality of a soluble protein can only be fully grasped when its aqueous interface becomes an integral part of the structural analysis. Furthermore, the acknowledgment of how exquisitely the structure and dynamics of proteins and their
aqueous environment are related attests to the overdue recognition that biomolecular phenomena cannot be grasped without dealing with interfacial behavior at multiple scales. This is essentially the dictum that guided the writing of this book.

The author deals with biological interfacial phenomena in his own unique and transformative way. He introduces what he calls “epistructural tension“, a concept that relates to the reversible work needed to span the aqueous interface that envelops the structure of a soluble protein.  Epistructural tension is, he argues, key to biology when examined at the molecular scale since it steers molecular associations, drives protein folding and functionalizes water at the interface, prompting a substantial revision of biochemical mechanism. The impact of this concept reaches distant fields like enzymology, structural biology and pharmacological design, and the book exploits it within an incredibly broad spectrum of possibilities, spanning vast conceptual territory, from statistical physics to molecular-targeted therapy. For example, Chap. 1 introduces a statistical thermodynamics framework to handle the aqueous interface of a protein, while Chap. 17 describes the epistructure-based design of kinase inhibitors with controlled multi-target activity to treat cancer metastasis and overcome drug resistance. In spite of this astonishing latitude of interdisciplinary research, the conceptual progression remains smooth throughout the presentation, as the reader is guided by Fernandez’s characteristically supple prose. The book can serve as a textbook, as originally intended, and also as an advanced monograph for practitioners in drug design or molecular-targeted therapy interested in the translational aspects of their art.

Ariel Fernandez, 2016

Ariel Fernandez in 20016

The book builds on original and highly meritorious research previously reported in professional journals by the author. Here are some quotes on different aspects covered in the new book:

On the discovery of the dehydron: “This is a very radical way of thinking. This is an experiment that actually backs up that radical way of thinking and that’s what’s striking about it.” Peter Rossky, interviewed by the University of Chicago News Office

On the pharmacological designs guided by epistructural patterns: “With tools such as those of Ariel Fernandez, the future certainly looks bright for constructing ever-better agents that can be combined safely and effectively to manage and eventually cure many forms of human cancer.” George Demetri, Review on the work of Ariel Fernandez commissioned by the Journal of Clinical Investigation

On the medical implications of the work of Ariel Fernandez: “The biggest message from this paper by Ariel Fernandez et al. is that a cardiotoxic cause can be identified and steered away from. There are hundreds of agents in development that could benefit from this research.” Thomas Force, interviewed by the Royal Society of Chemistry

On the Ariel Fernandez’s dehydrons as structural markers for molecular evolution: “One aspect of Fernandez’s research that is potentially groundbreaking is the observed tendency of proteins to evolve a more open structure in complex organisms. …This observation fits with the general theory that large organisms with relatively small population sizes — compared to microbes — are subject to the vagaries of random genetic drift and hence the accumulation of very mildly deleterious mutations… In principle the accumulation of such mutations may encourage a slight breakdown in protein stability. This, in turn, opens the door to interactions with other proteins that can return a measure of that lost stability. These are the potential roots for the emergence of novel protein-protein interactions, which are the hallmark of evolution in complex, multicellular species… In other words, the origins of some key aspects of the evolution of complexity may have their origins in completely nonadaptive processes.Michael Lynch interviewed by Rice University News Office on the work of Ariel Fernandez.

On Biomolecular Interfaces, the previous title by Ariel Fernandez introducing epistructural tension for the first time: “In this book author Ariel Fernandez introduces conceptual advances in molecular biophysics and translates them into novel pharmacological technologies. In so doing, he creates a new discipline named “epistructural biology”, focusing on the reciprocal interactions between interfacial water and protein structure. The epistructural biology approach enables researchers to address core problems in molecular biophysics such as the protein folding problem. The book surveys powerful theoretical /computational resources in epistructural biology to tackle fundamental problems, such as the physico-chemical basis of enzyme catalysis and the therapeutic disruption of protein-protein associations. The latter is recognized by many as the biggest challenge in structure-based drug discovery. A multi-disciplinary approach is exploited to engineer drugs, enabling decisive advances in molecular medicine with a tight control of drug selectivity. This book may well be Ariel Fernandez’s greatest contribution and its conceptual insights will enlighten and inspire readers. The author is also a masterful expositor which makes the book a pleasure to read.” Valentin Andreev.

Another comment on the previous title by Ariel Fernandez: “First and foremost, this book addresses an issue that is very important in protein research, namely, the interactions between a protein molecule and its surrounding water environment. This very complicated relationship is often simplified or ignored in molecular modeling. Such an ill-considered strategy simplifies the model but leads to unrealistic predictions of molecular behaviour. By contrast, this book introduces the reader to Epistructural Biology, a model that covers various important aspects of the protein-water interaction. The model is explained with an articulate clear writing style and backed up with enough mathematics to put the ideas on a firm theoretical foundation. The book is suitable for advanced undergraduate and graduate students. To help the student assimilate the ideas, the chapters include several problems with solutions. This is an excellent introduction for students wanting to get a start in Epistructural Biology.” Forbes Burkowski.

Biomolecular Interfaces may well be Ariel Fernandez‘ most authoritative work. In Chapter 3 we find a semiempirical solution to the protein folding problem, in chapter 5 we find a way to disrupt protein-protein interactions for therapeutic purposes (a major challenge in the pharmaceutical industry), in chapter 7 we find Ariel Fernandez’ striking new finding: the catalytic role of packing defects in proteins, ushering a new biotechnology. The applications to drug design in the remaining chapters bring us many surprises, including a quantum mechanics development of the wrapping drug-target interactions pioneered by the author. Ariel Fernandez’ Biomolecular Interfaces is enjoyable and rewarding. Its conceptual richness, style, and breadth of interwoven disciplines, from Statistical Thermodynamics to Molecular Medicine, make it a valuable asset.” Xi Zhang.

To conclude, here is a biosketch of the author as provided by Springer:

Ariel Fernandez (born Ariel Fernandez Stigliano) is an Argentine-American physical chemist and mathematician. He obtained his Ph.D. degree in chemical physics from Yale University in record time. He held the Karl F. Hasselmann endowed chair professorship in engineering at Rice University and was a professor of bioengineering until his retirement in 2012. To date, he has published over 350 scientific papers in professional journals including Physical Review Letters, PNAS, Nature, Genome Research, and Genome Biology. Ariel Fernandez has also published two books Transformative Concepts for Drug Design (2010) and Biomolecular Interfaces (2015), both with Springer, and holds two patents (US 8,466,154 and 9,051,387) on biotechnological innovations. He is currently involved in research and entrepreneurial activities at various consultancy firms.


Ariel Fernandez Books

Three recent books by Ariel Fernandez



Selected publications of Ariel Fernandez (ResearcherID):

Rewriting the Mechanisms of Biological Chemistry: Dehydrons as Chemical Species

If you peruse any of the increasingly bulkier biochemistry textbooks you will notice that a large portion of the reactions depicted correspond mechanistically to transesterifications. Typically in these reactions, nucleophilic attacks are responsible for the breaking and forming of bonds at the catalytic site of the enzyme/substrate transient complex. Yet, something does not look quite right: the chemical formula “H2O” appears in the elementary steps [1] but seems to signify something chemically quite different from what we would identify as water. The underlying acid-base chemistry is usually completely inconsistent with the chemical behavior in a bulk aqueous environment. For example, the functionalization of a nucleophilic group, here generically denoted AH, through deprotonation is often claimed to involve proton transference from AH to water. Yet, at least according to basic chemical intuition, hydronium is invariably more acidic than AH, and so unlikely to accept its proton. Also, the relay mechanisms for proton transference in enzymes – as in the so-called “catalytic triads” [1] – are typically completely at odds with the propensities for proton acceptance as dictated by the respective pKa’s of the groups involved. For instance, aspartate is often shown to nucleophilically functionalize a vicinal histidine by deprotonating it, something completely unrealistic in everyday chemistry.

Recent work by this author entitled “Acid-base chemistry of frustrated water at the protein interface” squarely addressed these paradoxes by adopting an approach that may alter the mechanistic picture of biological chemistry and prompt a rewriting of biochemical reactions in a way consistent with the rules of chemistry. The key point in this paradigm shift is that frustrated water partially occluded by structural defects at the protein interface is shown to turn into a chemical base, a species with radically different chemical properties from what chemists typically mean when they write “H2O” in a chemical reaction. In other words, interfacial water is biochemically functionalized into a new chemical species by nearby defects on the enzyme structure known as dehydrons (脱水元, 中文名)  [2-4]. In this way, dehydrons become catalytic enablers and stimulators of biochemical reactions, realizing an idea first advanced in Ariel Fernandez’ book “Biomolecular Interactions“.

[1] Alan Fersht (1998) Structure and Mechanism in Protein Science. W H Freeman, 1st edition.

[2] Ariel Fernandez (2015) Packing defects functionalize soluble proteins. FEBS Letters 589, 967-973.

[3] Weishi Meng (2015) Ariel Fernandez at the Center of Transformative Biotechnology. Science Transparency, 3/14/2015.

[4] Website for Ariel Fernandez Consultancy.


Structure-based drug discovery without structure: Working around the paradox to cure heart failure

Transcript on presentation by Ariel Fernandez for Drug Discovery Today (doi:10.1016/j.drudis.2015.10.006)

Drug discovery has been focusing for some time on protein-protein (PP) associations, the basic molecular events in biology. The recruitment of protein complexes is required to initiate and propagate signaling cascades, regulate enzyme activity, articulate and control mechanistic processes involving molecular motors, etc. When such associations engage altered binding partners, complex formation may lead to deregulation of biological functions and the drug-based disruption of the aberrant associations may represent new therapeutic opportunities.

However, the disruption of protein-protein interfaces (PPIs) remains a major challenge in drug discovery. The problem becomes daunting when the structure of the target protein is unknown and is further complicated when the interface is susceptible to disruptive phosphorylation. Based solely on protein sequence and on information on phosphorylation-susceptible sites within the PPI, a new technology was developed to identify drug leads to inhibit protein associations. The technology is described in the contribution “Drug leads for interactive protein targets with unknown structure” by Ariel Fernandez and Ridgway Scott, to appear in Drug Discovery Today.

The novel technology is illustrated by a patented invention to treat heart failure. The success of this technology as implemented by Drs. Richard L. Moss and Ariel Fernandez shows that it is possible to generate drug leads in the absence of target structure.

Richard L. Moss and Ariel Fernandez, inventors in US patent 9,051,387

Richard L. Moss and Ariel Fernandez, inventors in US patent 9,051,387

In cardiomyocytes, the myosin- myosin-binding protein C (MyBP-C) association creates a molecular brake on contractility imposed by the repressive activity of the unphosphorylated form of MyBP-C on myosin. In heart failure, MyBP-C is phosphorylated minimally or not at all due to down-regulation of β-adrenergic receptors. Since phosphorylation of MyBP-C improves contraction, US patent 9,051,387 proposed to target the phosphorylation site on MyBP-C with a pharmaceutical designed to disrupt its interaction with myosin and thereby improve cardiac function. This problem involves designing an optimal MyBP-C-derived peptide. The peptide contains the motif responsible for interaction with myosin and hence disrupts the MyBP-C-myosin association as required for therapeutic action. The myosin-binding peptide-based therapeutic agent may be identified based on the premise that disruption of the myosin-MyBP-C interface would release the molecular brakes on cardiomyocyte contractility imposed by the repressive activity of the unphosphorylated form of MyBP-C on myosin.

The 3D-structure of the 11-domain MyBP-C is unknown, and therefore it was decided to design the peptide based on the output from a sequence-based predictor of native disorder. The peptide was developed based on a prediction of the dehydron-rich region that constitutes the putative myosin-binding site. To identify the peptide sequence, the inventors examined a region in the twilight zone between order and disorder. In this way, it became possible to identify the region containing the operational phosphorylation sites in cMyBP-C and determine the sequence of the patented peptide that may be used as a lead to the therapeutic agent to treat heart failure. The invention has been shown to significantly increase cardiac contractile force and frequency in the failing heart.

Crisis of Trust in Science: How Much Out There is for Real?

Too much of what is published is either wrong or trivial!” I still vividly remember this admonition by the eminent mathematician Shizuo Kakutani delivered to a class on functional analysis at Yale University. My eyes were wide open, I had just entered graduate school and it was the fall of 1981.

Dr. Ariel Fernandez in his Yale days.

Dr. Ariel Fernandez in his Yale days.

How much out there can you trust as a scientist? How much of the published scientific record can withstand the test of time or should be swiftly withdrawn? What percentage of your own scientific claims is likely to be debunked during your lifetime? These are looming questions that often haunt researchers early in their careers.

Reprogramming differentiated cells into stem cells by adding acid and a few other chemicals (stimulus-triggered acquisition of pluripotency, or STAP) seemed almost too good to be true. Sure enough, STAPs didn’t fly for long. Nature, the journal where the striking discoveries were announced, went at considerable lengths to spot potential issues after the results met skepticism right from the get-go. It was quickly realized that STAP cell research would not pass the acid test of science.

The more recent claims on the astronomical signature of such esoteric entities like cosmic inflation and gravitational waves seemed blockbusters in their own right, only to be reinterpreted as artifacts due to cosmic dust. The scientists that heralded the discoveries as crucial to unveil the mysterious Big Bang ripples and to corroborate Einstein’s predictions were now trying to distance themselves from the recent claims.

An alarming proportion of the research that people have tried to replicate has proven to be irreproducible. And it is sometimes very difficult to reproduce research results. I still remember the work by one of the coworkers of Nobel laureate Manfred Eigen at the Max Planck Institute in Goettingen, Germany, that had elicited skepticism as it seemed to contravene the central dogma of biology (a postulate about the directionality of the flow of biological information). The results published in the journal Nature seemed to support the existence of a flow of information from protein to RNA, counter to the established RNA-to-Protein directionality. As it turns out, the biological material that needed to be handled to reproduce those experiments was so difficult to work with that the researcher in question and his technician, both skillful experimentalists, needed to be flown over (often across the Atlantic) to whatever lab was claiming irreproducibility in order to perform the experiment in situ. It worked every time!

How thoroughly should you check your claims? If the news are truly spectacular, many labs will surely try to reproduce the work and, some would say, if you don’t have great news to convey, why bother doing the work in the first place? I suspect that the vast majority of mistakes are simply never spotted or withdrawn. Faulty research only comes to light because there is enough incentive for other scientists to try to replicate the research. The vast majority of research findings are simply never tested by other groups.

Again, how much out there is likely to be faulty? As it turns out, we now have a-priori estimates of such a figure, and they surely paint a disturbing picture. In 2005, John Ioannidis, a professor of medicine at Stanford University, published a paper entitled “Why most published research findings are false.” Ioannidis used statistical arguments and a set of common-sense assumptions to infer the likelihood that a given scientific paper contains false results. His conclusions are based on rigorous mathematics and statistics and are extremely troubling. Under a great variety of conditions, prejudices and interests, most scientific claims are false and they are overwhelmingly likely to represent “measures of prevailing biases” rather than pristine novel truths.

In regards to the financial interests that may be at play within this bleak picture, it is of course too tempting to assume that pharmaceutical companies would tend to publish results that highlight the therapeutic efficacy of their products and cite supporting studies, while placing those that raise doubts under the rug. Hopefully, this is not the case.

This crisis of trust demands that we regard the scientific process in a different light, not as an infallible series of hits but rather as a modest progression of provisional attempts at approaching truth. Strangely, this takes us back to the way Newton regarded science: Truth lies in front of our eyes like a vast ocean and we would be lucky to find a few pebbles at the beach.

The crisis of trust is not going to be resolved by beefing up journals with peer reviewers or by opening the gates of post publication critique in blogs where anybody is entitled to his or her neurosis. Science only gets trustworthy knowledge through a long and convoluted curation that is sometimes referred to as “the test of time”. If a good result is out there, it will pass the test and will be sooner or later incorporated to the real corpus, the one that matters. As any scientist worth his/her salt knows, the body of knowledge is far smaller than the published record.

Ariel Fernandez held the Karl F. Hasselmann Chaired Professorship in Bioengineering at Rice University until his retirement in 2011.


阿列尔·费尔南德斯(Ariel Fernandez,出生名 阿列尔·费尔南德斯·斯提格里亚诺, 出生于1957年4月18日)是一位阿根廷美国双重国籍的物理化学家[1],1984年在耶鲁大学获化学物理专业博士学位,曾在马克思-普朗克研究所在诺奖得主Manfred Eigen和Robert Huber的指导下从事博士后研究,后在美国莱斯大学任Karl F. Hasselmann讲座讲授,期间曾指导来自两名中国的留学生张曦陈建平的博士学位论文,2011年从莱斯大学退休后开始在瑞士的巴塞尔学院继续从事研究工作,同时创建咨询公司Ariel Fernandez ConsultancyAF Innovation为企业提供咨询服务。

Ariel Fernandez



阿列尔•费尔南德斯多个领域的顶级学术期刊上发表文章,包括:代数、动力系统理论、统计力学、化学物理、界面现象、药物设计、癌症治疗和结构生物学视角下的分子进化。他的部分发表成果被收录在Google Scholar CitationsResearchGate。他曾在国际重要期刊上发表过350篇学术论文,包括:Proceedings of the US National Academy of Sciences, Annual Reviews of Genetics, Nature, Physical Review Letters, Genome Research,其科研成果曾被 Nature, Nature Reviews Drug Design, Chemistry World (UK Royal Society), Scientific American等著名期刊评述。阿列尔•费尔南德斯著有一部学术著作,持有两个药物治疗方面的专利。

阿列尔•费尔南德斯在药物设计领域的一部分最重要的研究成果属于转化医学。他建立了被称之为dehydron的物理化学模型用于描述蛋白质分子的一种结构奇点,并将此模型用于进行药物特异性筛选从而设计更为安全的药物。基于dehydron理论,阿列尔•费尔南德斯发明了分子工程中的“包裹技术”(wrapping technology)。“包裹技术”让药物设计人员能够根据蛋白质靶点的dehydron分布特点来设计药物,从而达到更好的特异性。“包裹技术”及其应用在阿列尔•费尔南德斯的著作“Transformative Concepts for Drug Design: Target Wrapping”(Springer-Verlag, Berlin, 2010)中有详细描述。


  • “Transformative Concepts for Drug Design: Target Wrapping”, by Ariel Fernandez (ISBN 978-3642117916, Springer-Verlag, Berlin, Heidelberg, 2010).[2]
  • “Biomolecular Interfaces: Interactions, Functions and Drug Design”, by Ariel Fernandez (ISBN-10: 3319168495, ISBN-13: 978-3319168494, Springer; 2015 edition)..[3]


On “Promoting an Open Research Culture” (Science Magazine)

Dr. Ariel Fernandez

Dr. Ariel Fernandez

On 26 June 2015, Science magazine published an article in its section “Policy Forum” entitled “Promoting an Open Research Culture”  (B. A. Nosek et al. Science, Vol. 348, pp. 1422-1425, DOI: 10.1126/science.aab2374). The article and two related pieces (“Self-correction in science at work”, and “Solving reproducibility“) published in the same issue seem to have been inspired by the perception that there is an irreproducibility crisis affecting science. This delution has been installed in the media by some journalists and other outsiders to science.

Prof. Ariel Fernandez opined on the subject. His pronouncement is featured in Science. The contribution is reproduced below in accord with Terms and Conditions on User Submissions to Science:

Some journalists and some science outsiders have installed the belief that science is in the midst of a reproducibility crisis. These people are being listened to, at least by some editors, while they feverishly advocate for higher standards of transparency in regards to the way in which scientists conduct and report their findings. The underlying misconception that led to this delusional thinking may well end up sliding into hysteria if scientists keep taking advice from outsiders on how to conduct their business. The misconception sprouts from the odd notion that scientific publications are meant to report monolithic truths that must withstand the acid test of time. Nothing further from the truth, and while scientists comply and try to raise the bar on transparency and accountability, they better take steps to debunk the myth that research papers distill anything other than provisional assertions subject to endless revision.

Much of the science reported is a-priori likely and expected to be faulty merely on statistical grounds. John Ioannidis, a professor of medicine at Stanford University, wrote in 2005 a paper in the journal PLoS Medicine entitled “Why most published research findings are false” (…) where, using statistical arguments, he estimated that the likelihood that a scientific paper contains false results is nearly 50%. His analysis reveals that under a great diversity of conditions, most scientific findings are likely to simply represent “measures of prevailing biases”. This statistical study was conducted with the utmost rigor and prompts us scientists to regard research reports with lower expectations, more in the context of a progression of provisional attempts at attaining an independent pristine truth. And please, please, let us focus on running our business ourselves, or we will have no one else to blame for the current crisis, be it real or delusional.

Dr. Ariel Fernandez Stigliano is the former Karl F. Hasselmann Professor of Bioengineering at Rice University.


阿列尔·费尔南德斯 (Ariel Fernandez Baidu biosketch)

Coverage at Science Transparency

Follow Ariel Fernandez on Twitter

Ariel Fernandez interviewed and featured in Science Transparency

New treatment for heart failure: US Patent 9,051,387 by Richard Moss and Ariel Fernandez

The recently awarded US patent number 9051387 describes the first therapeutic disruption of a protein-protein association using a rationally designed man-made ligand, a challenge considered the holy grail in drug discovery. This invention by Richard Moss and Ariel Fernandez provides basically a treatment of heart failure. At the molecular level, the effect of the drug is the disruption of the association between myosin and its modulator MYBP-C using a competitive man-made ligand. The target was identified by cardiologist Richard Moss, while the drug itself was created by Ariel Fernandez.

US patent 9,051,387 by Richard Moss and Ariel Fernandez. The patent awarded June 9, 2015 offers a novel treatment for heart failure

US patent 9,051,387 by Richard Moss and Ariel Fernandez. The patent awarded June 9, 2015 offers a novel treatment for heart failure

This invention is featured at: US Patent and Trademark Office page, Espacenet page, Description by the University of Wisconsin-Madison, Ariel Fernandez Consultancy,, Ariel Fernandez’s professional page. This patent marks the dawn of the new paradigm for drug discovery based on epistructural biology, the new discipline introduced by Ariel Fernandez.

You may read the press release for Richard Moss and Ariel Fernandez’ patent US9051387 as featured in YahooMarketWatch, or in the original form prior to distribution in WebWire.



CV for Ariel Fernandez (updated May 18, 2015)


“Biomolecular Interfaces: Interactions, Functions and Drug Design”, the Latest Book by Ariel Fernandez

A new book by Ariel Fernandez has made its appearance on April 21, 2015. It is entitled “Biomolecular Interfaces: Interactions, Functions and Drug Design“. The publication particulars are:


The book consists of fifteen chapters and covers vast intellectual territory, from statistical thermodynamics to molecular medicine. Its foreword has been written by Prof. Richard L. Moss, the eminent cardiologist from Wisconsin who is a coninventor with Ariel Fernandez in a recent patent to treat heart failure. All in all, the book may place Ariel Fernandez at the center of a veritable biotechnological transformation.

Foreword by Richard L. Moss

The book deals with a largely overlooked area of molecular biophysics that is likely to have strong impact on molecularly targeted medicine and drug design:the aqueous interface of a soluble protein.  Foundational knowledge is presented in the first 7 chapters and enables the reader to effectively tackle major problems in biophysics, such as the protein folding problem and the therapeutic disruption of protein-protein associations.  These advances have been heralded by others, as is evident, for example, in this review published in Scientific American.

The remaining 8 chapters deal with medical applications mostly centered on rational drug design guided by the interfacial patterns of the protein targets.  Some of these advances involve reworking anticancer drugs to make them safer and less toxic and to control their specificity, all of which are reviewed in great detail.  This novel type of design was enthusiastically received by eminent physician scientists such as Thomas Force (Vanderbilt University) and was also covered in very promising terms for example in this review by Harvard oncologist George Demetri.  Quoting Dr. Demetri: “The first generation of kinase-inhibitory drugs such as imatinib and sunitinib have already provided patients with life-saving therapeutic options, and with tools such as those described by Fernández et al., the future certainly looks bright for constructing ever-better agents that can be combined safely and effectively to manage, and eventually cure, many forms of human cancer”.  These seminal advances are further enriched in the book with a description of novel molecular design concepts that enable us to therapeutically disrupt protein-protein interfaces.  This problem is considered to be a holy grail of molecular targeted therapy.  Therapeutic opportunities stem from the advances described in the book.  One illustration is provided in the potential treatment of heart failure by disrupting a myosin association with a myosin-regulatory protein, an invention with a pending patent by this reviewer (Richard Moss) and the author of the book.

All in all, the book reports considerable conceptual novelty rooted in fundamental knowledge that needs to find its way into the pharmaceutical discovery and development pipeline, in particular in the hit-to-lead and lead optimization phases.  Paraphrasing George Demetri, we conclude that the approach by Fernández and coworkers holds great promise for customized development of rationally designed therapeutic agents.

Richard L. Moss, Ph.D., Rennebohm Professor of Cell and Regenerative Biology, Dean, University of Wisconsin School of Medicine and Public Health


The decades that followed the successful forays in structural biology have
witnessed a veritable deluge of research publications in the next frontier discipline:
molecular biophysics. Despite much effort, the core problems in the field remain
stubbornly open and the field has not enjoyed, at least so far, the meteoric level of
success of structural biology. The stakes are high, the science is loud, and yet, the
signal-to-noise ratio in the conveyance of information remains deceptively low. In
spite of enticing promises, it is felt that we are nowhere near cracking the protein
folding problem from first principles, that we are far from unraveling the physical
basis of enzyme catalysis and protein associations, and that we are still
unable to engineer therapeutic drugs based on our understanding of molecular
interactions. In regards to the latter problem, drug discovery seems riskier than ever,
with projects routinely terminated at mid-stage clinical trials, new targets getting
harder to find, and therapeutic agents recalled due to unanticipated health threats or
idiosyncratic side effects in patient subpopulations. The vast and seemingly endemic
problems of the pharmaceutical industry are not confined to the scientific realm
but the latter has much to do them. Properly harvesting and ultimately exploiting
the output of structural biology to make more efficacious and safer drugs has proven
to be much more difficult than originally thought. This rather grim reality has
motivated the writing of this book as it keeps reminding us that conceptual
breakthroughs in the realm of molecular biophysics are sorely needed.

The book focuses on a vital area of biophysical research that has been—in the
author’s view—substantively overlooked if not relegated, an area from within many
of the needed breakthroughs are likely to sprout: the physics of biomolecular
interfaces. The book advocates its paramount relevance to tackle some of the core
problems in molecular biophysics in a unified systematic manner. To this effect, the
book introduces powerful theoretical and computational resources and is set to
inspire scientists at any level in their careers determined to address the major
challenges in the field.

The acknowledgment of how exquisitely the structure and dynamics of proteins
and their aqueous environment are entangled attests to the overdue recognition that
biomolecular phenomena cannot be effectively understood without dealing with
interfacial behavior. There is an urge to grasp how biologically relevant behavior is
mediated and affected by the structuring of biomolecular interfaces. This book
squarely addresses this need, heralding the advent of a new discipline that the
author has aptly named epistructural biology. This field may be broadly described
as the physicochemical study of the reciprocal influence between water and
biomolecular structure across the interface. Given its scope, the book ends up
covering vast intellectual territory. It has to, because the subject is highly
demanding and requires a multidisciplinary approach.

With the advent of sophisticated techniques for probing and modeling
biomolecular systems, it seems likely that epistructural biology will emerge as a
vigorous area of research, impacting core areas of biophysics, including protein
folding, enzyme catalysis, protein associations, and drug/ligand design.

Since the days of J.W. Gibbs or perhaps earlier, physical chemists have realized
that where different phases meet, unusual things are likely to happen. Even for
interfaces modeled as sharp discontinuities between bulk phases—where, say,
a liquid meets a solid—the mere solution of continuity generates surface-associated
phenomena such as interfacial tension. The free energy cost of spanning the interface
makes the latter a locus for unexpected phenomena. One wonders whether, had the
pioneers of surface physics been confronted with the complexity of biological
interfaces laid bare in the recent decades, they may not have turned to other projects
in despair at their ungainliness.

The closer we look, the greater the complexities of biological interfaces appear
to be. Episteric (“around the solid”) water relinquishes its bulk-like character and
even fails to align with the electrostatic field due to tight geometric confinement
coupled with short-range intermolecular forces. These deviations from bulk properties
can enhance the chemical inhomogeneity of protein surfaces by altering the
dielectric properties of interfaces in unfathomable ways. Furthermore, biological
interfaces may be significantly enriched in ions relative to bulk water, an effect with
profound consequences for core biophysical phenomena. Even the most basic
questions such as whether episteric water is acidic or basic are still subject to

Interfaces have long been recognized as central to the chemical sciences but
there has been no systematic, cogent effort to understand them, let alone deal with
them in a biochemical context. This book squarely addresses this need and shows
that a masterful understanding of epistructural behavior is of the essence to address
the challenges that have proven unyielding to research efforts.

Recognizing that practitioners may not be familiar with biomolecular interfaces,
the book first introduces the subject at a reasonably elementary level, exploring
its relevance for protein interactions, protein folding, and catalytic function
(Chaps. 1–7). The remaining eight chapters are devoted to molecular targeted
medicine and therapeutic drug design based on the molecular understanding gained
in the first seven chapters. The book first explores biomolecular interfaces from a
physicochemical standpoint, drawing basic relationships between interfacial water
and the structure of soluble proteins (Chap. 1). The analysis leads to the concept of
dehydron, a protein structural defect that causes interfacial tension. Chapter 2
further deals with the physicochemical underpinnings of interfacial tension, demonstrating
its paramount relevance to understand protein associations. Chapter 3
deals with the steering role of the aqueous interface and interfacial tension in the
protein folding process, providing the first semiempirical solution to the protein
folding problem. Chapter 4 draws relations between interfacial tension and protein
hydration patterns that serve as blueprints for epistructure-based drug design.
Chapter 5 examines large concentrations of packing defects (dehydrons) as causative
of misfolding and aberrant aggregation phenomena and explores the connection
between disorder propensity, misfolding, and dehydron concentration. An
exercise in this chapter deserves particular attention as it leads the reader to discovering
a therapeutic disruption of a protein–protein interface based on rational
design, a holy grail in the field. Chapter 6 explores biomolecular interfaces from an
evolutionary perspective and highlights its relevance for the overarching goal of
achieving specificity in drug design. Chapter 7 deals with the chemical functionality
of biomolecular interfaces as enablers and stimulators of enzyme catalysis. This
chapter contains the highest level of novelty, as it presents the striking finding that
dehydrons prepare the aqueous interface for catalysis. Chapter 8 establishes a
selectivity filter for drug design based on the concepts introduced in Chap. 6.
Chapter 9 describes the redesign of a powerful anticancer drug guided by the
selectivity filter established in Chap. 8. Chapter 10 introduces a bioinformatics
analysis of biomolecular interfaces as universal markers for specificity and personalized
medicine achieved through the therapeutic interference with signaling
pathways. It emphasizes the usefulness of targeting biomolecular interfaces for
personalized molecular treatments tailored to cope with somatic or inherited
mutations that create constitutively deregulated functions. Chapter 11 deals with
dynamic aspects of drug design and drug-induced folding of the protein target,
focusing on dehydron induction. The dynamic concepts and their importance for
molecular engineering are illustrated by the redesign of imatinib into a JNK
inhibitor to treat ovarian cancer. Chapter 12 deals with drug combinations purposely
synergized to edit out side effects and constructed based on the dehydron
selectivity filters described in Chaps. 8–10. Chapter 13 introduces a systems biology
approach to the engineering of wrapping drugs and, consequently, introduces
the control of multi-target drug activity based on the selectivity filters previously
introduced. Chapter 14 introduces the novel modality of immuno-synergic drugs,
that is, anticancer kinase inhibitors redesigned to avoid compromising the immune
response while retaining anticancer activity. Finally, Chap. 15 deals with advanced
quantum mechanical treatments of biomolecular interfaces that empower the paradigm
of “drugs as dehydron wrappers.” These advanced quantum treatments lead
to significant improvements for drug design with the incorporation of halogens in
the chemical scaffolds.

The book is primarily intended as an advanced textbook that may be adopted at
the senior undergraduate level or graduate level and it also reads as a monograph for
practitioners. Fruitful reading requires a thorough background in physical chemistry
and biochemistry. The selected problems at the end of the chapters and the progression
in conceptual difficulty make it a suitable textbook for a graduate level
course or an elective course for seniors majoring in chemistry, biophysics, biomedical
engineering, or related disciplines. The material would be especially adequate
for courses dealing with the Thermodynamics and Physical Chemistry of
Biomolecular Systems, with Fields, Forces and Flows in Biological Systems, and
with Biological Engineering Design.

Excerpts from the Epilogue

This book covers broad knowledge territory, from statistical mechanics to
molecular medicine, and does so by exploring a vast interdisciplinary frontier:
biomolecular interfaces. By drawing relationships between protein structure and the
aqueous interface beyond, the book introduces a new subject aptly named
epistructural biology. The efficacy of this discipline to tackle core problems in
biophysics is demonstrably argued in Chaps. 1–7 and its pivotal role in the “hit-tolead”
and “lead optimization” phases of drug development is highlighted in the
remaining eight chapters of the book. Yet, as is often the case in science, a creative
solution to standing problems introduces new challenges as it shifts the research
frontier. Thus, epistructural biology redefines the established concept of molecular
recognition in light of the pivotal role of packing defects or dehydrons as recognition
elements, steers of protein folding and enablers of enzymatic catalysis. These
fundamental discoveries will surely invite studies leading to establish the role of
dehydrons as key players in redox enzymatic reactions. Of particular interest would
be to delineate the role of dehydrons as steers of redox-state–dependent organization
of water molecules at the interface with the protein structure in order to recruit
and steer proton transfer pathways (cf. Chap. 7). With the knowledge landscape
thus altered, new [meta-]problems [will surely] show up in the research horizon as
one explores what would now be termed the dehydron-mediated biomolecular
recognition of structured water.

Book highlights

Recent Amazon Review

Review Title: Epistructural Biology

By Forbes B. on May 14, 2015
Format: Hardcover

First and foremost, this book addresses an issue that is very important in protein research, namely, the interactions between a protein molecule and its surrounding water environment. This very complicated relationship is often simplified or ignored in molecular modeling. Such an ill-considered strategy simplifies the model but leads to unrealistic predictions of molecular behaviour. By contrast, this book introduces the reader to Epistructural Biology, a model that covers various important aspects of the protein-water interaction. The model is explained with an articulate clear writing style and backed up with enough mathematics to put the ideas on a firm theoretical foundation. The book is suitable for advanced undergraduate and graduate students. To help the student assimilate the ideas, the chapters include several problems with solutions. This is an excellent introduction for students wanting to get a start in Epistructural Biology.



Main Websites:

Scientific website

Ariel Fernandez Consultancy

AF Innovation

Ariel Fernandez ResearchGate

Ariel Fernandez Google Scholar Citations

Ariel Fernandez Wikipedia (Mandarin)

Ariel Fernandez Baidu Encyclopedia (Mandarin)

Ariel Fernandez Books

Current Positions

  • Senior Investigator, Argentine National Research Council (CONICET) (2011-). Argentine Institute of Mathematics (I. A. M.) “Alberto P. Calderón”, 1083 Buenos Aires, Argentina
  • Expert scientifique, Comité d’Evaluation Scientifique, Innovation Biomédicale, Agence Nationale de la Recherche, France (2015-)
  • Honorary Investigator, Collegium Basilea, Institute of Advanced Study, CH 4053 Basel, Switzerland (2006-)
  • Visiting Professor, National Tsing-Hua University, Hsinchu, Republic of China (2010-)
  • President, AF Innovation, SRL, a Pharmaceutical Consultancy (2010-).
  • Vicepresident and Chief Scientific Officer at Ariel Fernandez Consultancy, GmbH, a Biotechnology firm specialized in dynamic molecular design (2013-)

Past Appointments

  • Karl F. Hasselmann Chaired Professor of Engineering, Rice University, Department of Bioengineering, Rice University, Houston, TX 77005 (2005-2011)
  • Professor of Bioengineering, Rice University, 2005-2011 (retired)
  • Rice Research Professor (2011)
  • Adjunct Professor of Molecular Therapy, M. D. Anderson Cancer Center (UTMC) (2006-)
  • Adjunct Professor (2006-2008) and Visiting Scholar (2008-2012), Computer Science Department, The University of Chicago.
  • Senior Scientific Consultant, Eli Lilly and Company (2004- ).


  • Sr. Research Scientist, Max-Planck-Institut fuer biophysikalische Chemie, Division of Nobel Laureate Manfred Eigen, Goettingen, Germany, 1986-1989.
  • Research Associate (1985-1987), Visiting Senior Research Scientist (1994-1996), Princeton University.
  • Licenciado en Matematica (1980), Quimico (1979), Universidad Nacional del Sur, Bahia Blanca, Argentina.


  • Intelligence   IQ 151 (test# e2a3fa0b)
  • Citations*      3369
  • h-index*        30
  • i10-index*      94

(*) Source: Google Scholar Citations for Ariel Fernandez

Summary of Accomplishments

Ariel Fernández introduced what appears to be the correct formulation for self-organization in nonequilibrium thermodynamics by realizing that the thermodynamically relevant degrees of freedom must belong to a center manifold, an algebraically closed entity, and not to an attractor, as Ilya Prigogine previously assumed. He has provided a semiempirical solution to the protein folding problem by introducing the episteric tension, a measure of the distortion of the water structural matrix that requires a multi-scale theory of dielectrics. He rationally discovered a ligand that would competitively disrupt a protein-protein interface for therapeutic purposes (patent pending). He also managed to predict and control induced folding in drug-target associations. Together with Ridgway Scott, he introduced the dehydron, a structural defect in proteins that promotes its own dehydration. A dehydron is a meta-structural feature of relevance in drug design, enzyme catalysis and protein folding. Ariel Fernández determined and measured the dehydronic field, the mechanical equivalent of the dehydration propensity of a dehydron exerted on a test nonpolar molecule and orthogonal to the Coulombic field. His current efforts are devoted to show that dehydrons are endowed with a catalytic role as enablers and stimulators of enzymatic activity.

Awards and Previous Appointments

  • Camille and Henry Dreyfus Teacher-Scholar Awardee, 1991
  • Camille and Henry Dreyfus Distinguished New Faculty Awardee, 1989
  • John S. Guggenheim Memorial Foundation Fellow, 1995-1996
  • Consultant to U.S. Federal Government, NIH, Special Panel on Centers of Excellence in  Systems Biology, 2003-
  • National Cancer Institute (NCI) Reviewer. NIH Study Section RFA-07-005 “Advanced Proteomic Platforms and Computational Sciences for NCI Clinical Proteomic Technologies Initiative”, 2006-
  • Guest Professor, Institute for Protein Research, Osaka University, Japan, 2003
  • Visiting Senior Researcher, Max-Planck-Institut fuer Biochemie, Abteilung Robert Huber, Martinsried, Germany, 2000-
  • Visiting Senior Scientist, Institute for Nonlinear Science, University of California at San Diego, 1989
  • Managing Editor, Frontiers in Bioscience, Encyclopedia of Bioscience, 2006-
  • Editor, Journal of Biological Physics and Chemistry, Basel, Switzerland, 2000-
  • Fulbright Scholar, US Information Agency, 1999 and Fulbright Fellow, 1981
  • Alexander von Humboldt Foundation Awardee (1995)
  • Max Planck Society Scholar, Goettingen, Germany (1987-1989)
  • Feinberg Fellow, Israel, 1984-1985
  • Full Professor, Indiana University School of Informatics, 2003-2005.
  • Full Professor, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 2003-2005.
  • Elected Fellow, American Institute for Medical and Biological Engineering, 2006
  • Full Professor and Principal Investigator, UNS and Natl. Res. Council of Argentina, 1994-2003.
  • Medal “State of Buenos Aires” to the best graduate, Argentina, 1980
  • Deputy Governor, American Biographical Institute, 1998-
  • Co-organizer and Proceedings Editor of the Miami Bio/Technology Winter Symposium, Nature-sponsored, 1993.
  • Chair, “Resistance and Safety”/Kinase Inhibitors, Cambridge Healthtech Institute’s Sixth Annual “Discovery on Target” Symposium; October 20-23, Boston, MA, USA, 2008.
  • Honorary Member, Collegium Basilea, Institute for Advanced Study, Basel, Switzerland, 2006-
  • Adjunct Professor of Computer Science, The University of Chicago (2005-2008).
  • Editorial Board Member, Journal of Postgenomics: Drug & Biomarker Development – Open Access, OMICS Publishing Group, 2010-
  • Editorial Board Member, Journal of Bioengineering & Biomedical Science, OMICS Publishing Group, 2010-
  • Editorial Board Member, Journal of Metabolomics: Open access, OMICS Publishing Group, 2012-
  • Distinguished Scientific Leader Lecturer, Georgia Institute of Technology, 11/10/2010, Lecture title: “Evolutionary insights into the control of drug specificity”. URL:
  • Columnist at Project Syndicate, The World’s Opinion Page (2011-)
  • Editorial Board Member, Journal of Pharmacogenomics & Pharmacoproteomics, OMICS Publishing Group, 2015-
  • Expert scientifique, Comité d’Evaluation Scientifique, Innovation Biomédicale (CE18), Agence Nationale de la Recherche, France, 2015-

Legal Consultancies – Pharmaceutical Patent Litigation

  • Schiff/Hardin, LLP (Chicago-based Law Firm).
  • Racoczy, Molino, Mazzocchi and Siwik, LLP (Chicago-based Law Firm)

Recent Grant support, PI: Ariel Fernandez

  • NIH Grant Award 1R01 GM072614 from the National Institute of General Medical Sciences (NIGMS). Title: “Protein packing defects as functional markers and drug targets”. Total amount of award: $1.6million (2005-2009).
  • Eli Lilly and Company, Unrestricted research funds (2004-)


  • US 8,466,154 B2 (granted)

Ariel Fernández et al.: “Methods and Composition of Matter Related to Wrapping of Dehydrons”. Inventors: Ariel Fernández, William Bornmann, Gabriel Lopez-Berestein, Angela Sanguino, Zeng-Hong Peng, Anil K. Sood. Awarded: June 18, 2013.

  • US 20130345135A1 (pending)

Richard L. Moss and Ariel Fernández: “Inhibition of MYBP-C binding to myosin as a treatment for heart failure”. Inventors: Richard L. Moss and Ariel Fernández; Asignee: Wisconsin Alumni Research Foundation.


  • Author: Ariel Fernández

Title: “Transformative Concepts for Drug Design: Target Wrapping

Publisher: Springer, Heidelberg, Berlin (240 pages)

ISBN: 978-3-642-11791-6

Publication year: 2010.


  • Author: Ariel Fernández Stigliano

Title: “Biomolecular Interfaces: Interactions, Functions and Drug Design

Publisher: Springer, Heidelberg, Berlin (372 pages)

ISBN: 978-3319168494

Publication year: 2015.


Selected Recent Publications

Sources: ResearchGate, Google Scholar Citations, Baidu Encyclopedia (Mandarin) and Wikipedia (Mandarin)

  1. Ariel Fernández and Harold A. Scheraga: “Insufficiently dehydrated hydrogen bonds as determinants for protein interactions”, Proceedings of the National Academy of Sciences, USA 100, 113-118 (2003).
  1. Ariel Fernández and R. Stephen Berry: “Proteins with hydrogen-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis”, Proceedings of the National Academy of Sciences, USA 100, 2391-2396 (2003).
  1. Ariel Fernández and Ridgway Scott: “Adherence of packing defects in soluble proteins”, Physical Review Letters 91, 018102, 4 pages (2003).
  1. Ariel Fernández, Jozsef Kardos, Ridgway Scott, Yuji Goto and R. Stephen Berry: “Structural defects and the diagnosis of amyloidogenic propensity”, Proceedings of the National Academy of Sciences, USA 100, 6446-6451 (2003).
  1. Ariel Fernández, L. Ridgway Scott and R. Stephen Berry: “The nonconserved wrapping of conserved folds reveals a trend towards increasing connectivity in proteomic networks”. Proceedings of the National Academy of Sciences, USA 101, 2823-2827 (2004).
  1. Ariel Fernández, Kristina Rogale, L. Ridgway Scott and Harold A. Scheraga: “Inhibitor design by wrapping packing defects in HIV-1 proteins”. Proceedings of the National Academy of Sciences, USA 101, 11640-11645 (2004).
  1. Ariel Fernández and R. Stephen Berry: “Molecular dimension explored in evolution to promote proteomic complexity”. Proceedings of the National Academy of Sciences, USA 101, 13460-13465 (2004).
  1. Ariel Fernández: “Keeping Dry and Crossing Membranes”. Nature Biotechnology 22, 1081-1084 (2004).
  1. Florin Despa, Ariel Fernández and R. Stephen Berry: “Dielectric modulation of biological water”. Physical Review Letters 93, 228104 (4 pages) (2004). Featured in Nature (News and Views) 432, 688 (2004).
  1. Ariel Fernández: “Incomplete protein packing as a selectivity filter in drug design”. Structure 13, 1829-1836 (2005).
  1. Jianping Chen, Xi Zhang and Ariel Fernández: “Molecular basis for specificity in the druggable kinome: sequence-based analysis”. Bioinformatics 23, 563-572 (2007).
  1. Ariel Fernández et al.: “Rational Drug Redesign to overcome drug resistance in cancer therapy: Imatinib moving target”. Cancer Research 67, 4028-4033, Priority Report, Cover featured (2007).
  1. Ariel Fernández, et al.: “An anticancer C-kit kinase inhibitor is re-engineered to make it more active and less cardiotoxic”. Journal of Clinical Investigation 117, 4044-4054 (2007). (featured in Press Releases). Commentary by George Demetri: Structural reengineering of imatinib to decrease cardiac risk in cancer therapy. Journal of Clinical Investigation 117, 3650-3653 (2007).
  1. Ariel Fernández: “Molecular basis for evolving self-dissimilarity in the yeast protein interaction network”. PLoS Computational Biology 3, e226 (2007).
  1. Ariel Fernández, Xi Zhang and Jianping Chen: “Folding and wrapping soluble proteins: Exploring the molecular basis of cooperativity and aggregation”. Progress in Molecular Biology and Translational Science 83, 53-88 (2008).
  1. Xi Zhang, Alejandro Crespo and Ariel Fernández: “Turning promiscuous kinase inhibitors into safer drugs”. Trends in Biotechnology 26, 295-301 (2008).
  1. Ariel Fernández and Alejandro Crespo: “Protein wrapping: a marker for association, aggregation and molecular targeted therapy”. Chemical Society Reviews (Royal Society of Chemistry, UK) 37, 2373-2382, Tutorial Review (2008).
  1. Jianping Chen, Han Liang and Ariel Fernández: “Protein structure protection commits gene expression patterns”. Genome Biology 9, R107 (2008).
  1. Ariel Fernández, Soledad Bazán and Jianping Chen: “Taming the induced folding of drug-targeted kinases”. Trends in Pharmacological Sciences 30, 66-71 (2009)
  1. Ariel Fernández and Jianping Chen: “Human capacitance to dosage imbalance: Coping with inefficient selection”. Genome Research 19, 2185-2192 (2009).
  1. Ariel Fernández and R. Stephen Berry: “Golden rule for buttressing vulnerable soluble proteins”. Journal of Proteome Research (ACS) 9, 2643-2648 (2010).
  1. Larisa Cybulski, Mariana Martin, Maria Mansilla, Ariel Fernández and Diego de Mendoza: “Membrane Thickness Cue for Cold Sensing in a Bacterium”. Current Biology 20, 1539-1544 (2010). Editorially commissioned review by Kumaran Ramamurthi, Current Biology 20, R707-R709 (2010). Research Highlight in Nature Reviews/Microbiology: Lucie Wootton: “Bacillus takes the temperature”. Nature Reviews/Microbiology 8, 680 (2010).
  1. Ariel Fernández: “Nanoscale Thermodynamics of Biological Interfacial Tension”, Proceedings of The Royal Society A 467, 559-568 (2010).


  1. Ariel Fernández: “Variational mechanics of water at biological interfaces”. Fast Track Communication. Journal of Physics A: Math. Theor. 44, 292001 (2011).
  1. Ariel Fernández and Michael Lynch: “Nonadaptive origins of interactome complexity”. Nature 474, 502-505 (2011).
  1. Ariel Fernández, Christopher Fraser and L. Ridgway Scott: “Purposely engineered drug-target mismatches for entropy-based drug optimization”. Trends in Biotechnology 30, 1-7 (2012).
  1. Ariel Fernández: “Communication: Epistructural thermodynamics of soluble proteins”. Journal of Chemical Physics 136, 091101 (2012).
  1. Ariel Fernández: “Epistructural tension promotes protein associations”. Physical Review Letters 108, 188102 (2012). Reviewed in Physics (American Physical Society). Focus: “Proteins Hook up Where Water Allows”. Physics 5, 51 (2012). Reviewed in Chemical & Engineering News “Protein Binding Hot Spots”. Chemical & Engineering News 90 (20), 39 (2012)
  1. Ariel Fernández: “Comunication: Nanoscale electrostatic theory of epistructural fields at the protein-water interface”. Journal of Chemical Physics 137, 231101 (2012).
  1. Ariel Fernández Stigliano: “Breakdown of the Debye polarization ansatz at protein-water interfaces”. Journal of Chemical Physics 138, 225103 (2013).
  1. Ariel Fernández: “Supramolecular evolution of protein organization”. Annual Reviews of Genetics, in press (2015).
  1. Ariel Fernández: “The principle of minimal episteric distortion of the water matrix and its steering role in protein folding”. Journal of Chemical Physics 139, 085101 (2013).
  1. María Eugenia Inda, Michel Vandenbranden, Ariel Fernández, et al.: “A lipid-mediated conformational switch modulates the thermosensing activity in DesK”. Proceedings of the National Academy of Sciences USA 111, 3579-3584 (2014). Reviewed in Research Highlights – Nature Chemical Biology 10, 240 (2014)
  1. Ariel Fernández: “Synergizing immunotherapy with molecularly targeted anticancer treatment”. Drug Discovery Today 19, 1427-1432 (2014).
  1. Ariel Fernández: “Water promotes the sealing of nanoscale packing defects in folding proteins”. Journal of Physics: Condensed Matter – Fast Track Communications 26, 202101 (2014).
  1. Ariel Fernández: “How do proteins dry in water?” Journal of Physics: Condensed Matter – News Item, May 1 (2014). Published at:
  1. Ariel Fernández: “Communication: Chemical functionality of interfacial water enveloping nanoscale structural defects in proteins”. Journal of Chemical Physics 140, 221102 (2014).
  1. Ariel Fernández: “Packing defects functionalize soluble proteins” FEBS Letters 589, 967-973 (2015). Featured in Journal Cover.
  1. BOOK I

Author: Ariel Fernández

Title: “Transformative Concepts for Drug Design: Target Wrapping

Publisher: Springer, Heidelberg, Berlin (240 pages)

ISBN: 978-3-642-11791-6

Publication year: 2010.

  1. BOOK II

Author: Ariel Fernández Stigliano

Title: “Biomolecular Interfaces: Interactions, Functions and Drug Design

Publisher: Springer, Heidelberg, Berlin (372 pages)

ISBN: 978-3319168494

Publication year: 2015.

Book Foreword and Highlights


349. US 8,466,154 B2 (awarded)

Ariel Fernández et al.: “Methods and Composition of Matter Related to Wrapping of Dehydrons”. Inventors: Ariel Fernández, William Bornmann, Gabriel Lopez-Berestein, Angela Sanguino, Zeng-Hong Peng, Anil K. Sood. Awarded: June 18, 2013.

350. US 20130345135A1 (pending)

Richard L. Moss and Ariel Fernández: “Inhibition of MYBP-C binding to myosin as a treatment for heart failure”. Inventors: Richard L. Moss and Ariel Fernández; Asignee: Wisconsin Alumni Research Foundation.


  1. Ariel Fernández: “Human Evolution: No Easy Fix”. Project Syndicate (The World’s Opinion Page), Culture and Society Section, October 3, 2011. Published at:–no-easy-fix
  1. Ariel Fernández: “Structural Defects in Proteins May Function as Catalysts, Study Reveals”, Press Release: Discovery of the Catalytic Dehydron, WebWire, July 6, 2014.
  1. Ariel Fernández: “Protein Structural Defects Are Enablers and Stimulators of Enzyme Catalysis”. PR Newswire, July 14, 2014.

Reproduced in:  Yahoo News, The Wall Street Journal  – MarketWatch.


Related Reading

Ariel Fernandez complete CV (Updated 5/12/2015)

Book Flyer

Ariel Fernandez Biotechnology Consultancy

Ariel Fernandez Wikipedia (Mandarin)

Ariel Fernandez Wikipedia (English)

Ariel Fernandez Wikipedia (Spanish)


Ariel Fernandez at the Center of a Biotechnological Transformation (Reproduced from Science Transparency)

Interview reproduced from Science Transparency.

Ariel Fernandez (also styled as Ariel Fernandez Stigliano) is a physical chemist and mathematician and the former Karl F. Hasselmann Endowed Chair Professor of Bioengineering at Rice University. He got his Ph. D. in record time from Yale University under the guidance of Oktay Sinanoglu (who recently passed away according to Yale News). Completed in less than two and a half years, Ariel Fernandez’ doctorate is believed to be one of the fastest awarded by Yale in its 300 years history. His recent publications place him at the center of a veritable biotechnological transformation that we may term “dehydronic chemistry”. This interview seeks to assess the significance of protein dehydrons (the structural defects that Ariel Fernandez discovered at the University of Chicago) for enzymatic catalysis (Yahoo News, MarketWatch/Dow Jones & Co.). At the time when dehydrons were discovered, Peter Rossky, then the Marvin K. Collie-Welch Regents Chair in Chemistry at the University of Texas, Austin had this to say about the discovery to the University of Chicago News Office:  “It’s a very radical way of thinking”.

10551709_268061560049673_6019995725516727369_o (1)

Chinese audiences were familiar with the more “standard” role of dehydrons as promoters of protein-ligand associations ever since the memorable lecture by Ariel Fernandez at Academia Sinica in 2008 sponsored by Wen-Hsiung Li as featured in the poster below:

Ariel Fernandez lectures at Academia Sinica

The dehydron concept itself dates back to collaborative work between Ariel Fernandez and Harold Scheraga, published in the Proceedings of the National Academy of Sciences USA and work with L. Ridgway Scott, published in Physical Review Letters. Ultimately these concepts were translated by Ariel Fernandez and colleagues from M. D. Anderson Cancer Center into drug-based therapeutic agents with high specificity, as outlined in the patent “Mehods and Compositions Related to the Wrapping of Dehydrons” US 8,466,154. More recently, in another translation of the dehydron concept, Arie Fernandez and the eminent cardiologist Richard L. Moss invented a drug-based treatment for heart failure.

The portrayal of Ariel Fernandez as a beacon of scientific innovation is not new (check out this review) but his latest contributions add a new spin to the story. People were familiar with Ariel Fernandez’s dehydrons and their role in driving protein interactions by causing interfacial tension for nearly a decade. Their recently discovered “chemical role” puts dehydrons again at the frontline of scientific innovation, as a recent journal cover in FEBS Letters attests:

FEBS cover

The picture on display in the cover corresponds to Fig. 3 in Ariel Fernandez (2015) Packing defects functionalize soluble proteins. FEBS Letters 589:967-973.

WM: Almost every physical chemist and even people in related and distant disciplines is familiar with your name and with the dehydron concept. Yet, your name is coming up a lot more frequently lately, as attested by anyone who attended the Biophysical Society meeting and its Chinese counterpart (see your recent profile in Baidu Encyclopedia). What have you been up to that seems to be eliciting so much attention?


Source: Baidu Encyclopedia.

Ariel Fernandez: If you open any book on Biological Chemistry and examine those enzymatic reactions you will be left with a certain discomfort. You feel that something is not quite right. The reactants do not behave exactly as you were told they would. Most such reactions involve trans-esterifications that require nucleophilic attacks. These reactions are unthinkable if the chemical participants would be in the bulk. You are then told that the enzyme is “special” and that it offers a special environment conducive to the reaction.  But, what exactly is this special environment? What’s so special about it? That is the question I have addressed and the answer lies in the examination of the patterns of structural defects adjacent to the catalytic site.

To put it bluntly, enzyme catalysis is often viewed as a closed chapter in biochemistry or biophysics, where all the core issues have been essentially dealt with. Yet, problems related to the catalytic involvement of nano-structural features still hamper progress in the mechanistic understanding, and design of enzyme catalysts and inhibitors. Germane to these problems is the catalytic role of interfacial water confined by the nanoscale topography of the protein surface. That is exactly where I have now made substantive progress (I hope I got the story right). If I am right, much of the mechanistic literature on biochemical reactions would need to be rewritten, as the examples in my recent publication demonstrate.

Here you will find a voice presentation promoted at Elsevier, where I strive to get the point across.

WM: Are you saying those “defects” in the protein structure do more than shaping the active site?

Ariel Fernandez: I guess it all has to do with the realization that the structural defects in proteins known as dehydrons are endowed with a chemical role and participate as reactants in enzyme catalysis. Structural defects in proteins have a chemical function and that is news, maybe big news. [see Yahoo or Market Watch Press Releases]

WM: How can structural defects become reactants? I am somewhat familiar with heterogeneous catalysis in inorganic chemistry, where lattice defects in the crystal become crucial, but I guess you are referring to soluble proteins, quite another matter.

Ariel Fernandez: Yes, but there is a certain analogy. Dehydrons are ubiquitous at the active or catalytic site and intervene in the related enzymatic reactions by functionalizing the nano-confined interfacial water around them, locally inducing basicity at the interface. I have already conjectured this in a recent Communication  and now proved it in a Letter.

FEBS letters

WM: Sorry, now I am really confused. Why would the dehydron-promoted basicity enhance or even enable the enzymatic reaction?

Ariel Fernandez: Because the protein aqueous interface is essentially sculpted by the protein structure. The problem may be said to belong to the field of epistructural biology as I have outlined in my recent work. In this realm, one structural feature stands out: the so-called dehydron, a nanoscale defect that creates interfacial tension and thereby promotes protein associations. Dehydrons are backbone hydrogen bonds exposed to water due to nanoscale defects in the structure packing. Besides promoting dehydration, dehydrons also have a biochemical role that is proving to be exquisitely complementary: they turn nano-confined interfacial water into a chemical base, a proton acceptor. Thus, a dehydron in the proximity of a catalytic group purported to perform a nucleophilic attack enhances the catalytic potential of the latter through a chemical functionalization of vicinal water.

These two properties, combined with the fact that catalytic sites are invariably “decorated” with dehydrons, suggest a dual participation of dehydrons in catalysis: first, dehydrons prepare the solvent for enzyme activity and, after enhancing the enzyme nucleophilicity and turning the solvent into a better leaving group, dehydrons promote enzyme-substrate association in consonance with their dehydration propensity. This functional duality makes dehydrons both enablers and stimulators of enzyme catalysis. As you can surmise, this is an observation with paramount nano-biotechnological implications, especially in regards to what we may term “epistructure-based enzyme design”.

WM: There is of course structure-based enzyme design, people like Steve Mayo come to mind. Are you now proposing then “epistructure-based design”? On exactly what grounds?

Ariel Fernandez: Well, look at it this way: As dehydrons activate nearby catalytic groups to perform a chemical (nucleophilic) attack on the substrate, causing trans-esterification, they turn the nano-confined water into hydronium (H3O+, the product of proton acceptance). In turn, since the hydronium requires full hydration, it is easily removed from the active, thereby enabling enzyme-substrate association. This kind of dehydron-driven association is known as “wrapping”, and entails a thermodynamically favorable intermolecular “correction” of the structural defect. Thus, the dehydron may be regarded as a two-stroke molecular engine that promotes and sustains enzyme catalysis.

WM: Dehydrons promote protein associations, you are now saying they also have a chemical role and that both roles are complementary and essential to catalysis? Is that it?

Ariel Fernandez: Basically, yeah. This discovery may herald novel biomolecular design based on “dehydron enablers-stimulators”. These features may be created or removed though engineered mutations directed at fine-tuning the topography of the protein surface. In this way, we envision the possibility to activate or silence a catalytic site in a protein enzyme by respectively creating or annihilating its nearby dehydrons. On the other hand, novel drug-based enzyme inhibitors will emerge as dehydron agonists are targeted (wrapped) through engineered protein-drug associations. These possibilities were anticipated in my first book “Transformative Concepts for Drug Design: Target Wrapping” [here reviewed at Rice University]. They have been much further developed in my second book “Biomolecular Interfaces: Interactions, Functions and Drug Design” (foreword by Richard Moss, individual chapters here).

Biomol Interfaces

My latest book is in a sense a modern development of some work that I did back in my days at Yale jointly with my advisor Oktay Sinanoglu, a peerless genius who recently passed away. Oktay Sinanoglu became the youngest full professor at Yale in its modern history, I believe.


Picture from the Obituary for Oktay Sinanoglu by Ariel Fernandez published in Physics Today.

WM: I see, we could now envision novel molecular designs inspired by the “epistructural catalytic stimulation”.

Ariel Fernandez: Precisely! and this “epistructural stimulation” will foreshadow a generation of nanoscale-optimized enzyme catalysts and pharmaceuticals.

WM: The work of Ariel Fernandez does not need praise. His marvelous advances have already been heralded by others, as is evident, for example, in a recent review published in Scientific American. [reproduced in Nature]. The novel type of drug design he has introduced was enthusiastically received by eminent physician scientists such as Thomas Force (Vanderbilt University) and was also covered in very promising terms for example in a review by Harvard oncologist George Demetri.  Quoting Dr. Demetri:

“The first generation of kinase-inhibitory drugs such as imatinib and sunitinib have already provided patients with life-saving therapeutic options, and with tools such as those described by Fernández et al., the future certainly looks bright for constructing ever-better agents that can be combined safely and effectively to manage, and eventually cure, many forms of human cancer”.

These seminal advances are further enriched in his recent work with a description of novel molecular design concepts that enable us to therapeutically disrupt protein-protein interfaces.  This problem is considered to be a holy grail of molecular targeted therapy.  Therapeutic opportunities stem from the design concepts of Ariel Fernandez.  One illustration is provided in the potential treatment of heart failure by disrupting a myosin association with a myosin-regulatory protein, an invention with a pending patent by Richard Moss and Ariel Fernandez.

The work of Ariel Fernandez introduces considerable conceptual novelty rooted in fundamental knowledge that needs to find its way into the pharmaceutical discovery and development pipeline, in particular in the hit-to-lead and lead optimization phases.  Paraphrasing George Demetri we conclude that the approach by Fernández and coworkers holds great promise for customized development of rationally designed therapeutic agents.


Linked CV of Ariel Fernandez, updated May 18, 2015

Ariel Fernandez featured in Baidu Encyclopedia (Mandarin)

Ariel Fernandez at ResearchGate

Curriculum Vitae for Ariel Fernandez

The Peer Review Crisis by Ariel Fernandez

Rice University Faculty Catalogue

Ariel Fernandez Consultancy

Transformative Concepts for Drug Design: Target Wrapping, Book by Ariel Fernandez, Springer, 2010

Ariel Fernandez Professional Website

Post reproduced in AF Biophysics Blog




Awesome! In truth, a couple more experiments may be needed corroborating dehydron-based catalytic stimulation. Create a dehydron=enhance activity, that sort. After that I guess it’s just waiting by the phone for that early phone call from Scandinavia…


The breath of his contributions is pretty mind-boggling, from abstract algebra to biotechnological innovation. Just look at this:

The Morgridge Institute in Wisconsin introduces him as a beacon of pharmaceutical creativity:

Contrast these innovations with his 4 theorems in abstract algebra:

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