Ariel Fernandez's Rocky Biophysics

Missing science in biomolecular design

How NOT to handle the reproducibility crisis in science

Contributed by Dr. Ariel Fernandez Stigliano

Virtually everybody recognizes that science is facing a reproducibility crisis. Whenever a result elicits attention, be it because it is published in a high-impact journal, or better still because it is important, there is a high likelihood that others will attempt to reproduce it. They often fail, disturbingly often. Fortunately, this time around, the science establishment appears to be better prepared to handle the crisis and not let journalists and outsiders, especially the angry mob of Retraction Watch(ers), run the agenda for them. Thus, the US National Academy of Sciences has appointed a panel to assess the situation, while the Royal Academy of Arts and Sciences of the Netherlands (KNAW) has already issued a report and made a pronouncement.


Logo for the Royal Academy of Sciences of the Netherlands

In my modest opinion, the KNAW report could not be crasser. It proposes that considerable expenditures (between 5 and 10% of research funding) be destined to reproduce published scientific results.

The key question here is: who on earth is going to get motivated to conduct non-original research?  In today’s reality, the only valid motivation I can think of would be that the result under scrutiny is of fundamental value to the researcher and at the same time useful to further his or her research agenda. That is why the alleged STAP fabrication of Haruko Obokata and the late Yoshiki Sasai seemed so colossally stupid in retrospect: The result appeared to be so simple and so important that there surely would be legions of stem-cell researchers eager to reproduce it. How could Obokata get blindfolded by her own ambition in this way? The story had all the elements of a greek tragedy.

Haruko Obokata

Haruko Obokata as the STAP tragedy began to unfold.

There are of course a few people, like Joshua L. Cherry, who tend to obsessively invest in other researcher’s downfall (see Cherry’s frantic exchange with Prof. John Ioannidis), who would be also motivated to get involved in doing non-original research, but that would be for entirely the wrong reasons.



Book Review: A Mathematical Approach to Protein Biophysics, by Ridgway Scott and Ariel Fernandez

This book review is authored by Dr. Weishi L. Meng and reproduced from Science Transparency with permission.

A new book by Ridgway Scott and Ariel Fernandez is coming out. Its title “A Mathematical Approach to Protein Biophysics” (Springer, 2017) feels unusual at first. Why do we need a mathematical approach to understand proteins? Perhaps we need to be reminded that the major problems in molecular biophysics, such as the protein folding problem, have remained open because they demand a level of intellectual maturity that is not yet commonly found in the biological sciences and can be provided by applied math. And yet, few applied mathematicians have managed to say some relevant to biology partly because, rather than trying to find out how nature did it, they try to tell nature how to do it. Here I am referring specifically to the protein folding problem, whose first-principle solution was finally published by Ariel Fernandez in 2016 (Physics at the Biomolecular Interface, Chapter 3). When we think carefully about these monumental challenges, the need to engage mathematicians in the development of molecular biophysics hardly needs justification. The new book by Scott and Fernandez fulfills the need admirably, serving as a mathematician’s introduction to protein biophysics.


The publication particulars are:

Title: A Mathematical Approach to Protein Biophysics

Authors: L. Ridgway Scott, Ariel Fernández

Publisher: Springer International Publishing AG, CH

Pages: 284

Year: 2017

Price: 69.99 US dollars

Hardcover ISBN: 978-3-319-66031-8

Series Title: Biological and Medical Physics, Biomedical Engineering

Topics: Mathematical and Computational Biology



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

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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)


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