This blog is probably going to be about things that are opaque to our understanding in the field of molecular biophysics. Most of the important problems in this field, like the protein folding problem or rational drug design, remain open problems. Evidently, the science we are familiar with does not match these challenges. What are we missing then? This is what I wish this blog to be about.
The last decades have experienced a veritable deluge of research publications in molecular biophysics, yet most of the core problems in the field stand unsolved. The stakes are high, the science is loud, but the signal-to-noise ratio in the exchange of knowledge remains quite low. It is felt that we are nowhere near cracking the protein folding code from first principles, that we are quite far from unraveling the physico-chemical mysteries of enzyme catalysis and protein associations, and that we have failed to design therapeutic drugs in a rational and effective way. Conceptual breakthroughs are sorely needed and this blog will squarely address these needs.
Ariel Fernandez, biophysicist and mathematician
Honorary Member, Collegium Basilea, Institute for Advanced Study
Former Chaired Professor of Bioengineering at Rice University (retired in 2011).
Ariel Fernandez is an Argentinian-American chemist and mathematician specialized in rational drug design. He got his Ph. D. in Chemical Physics from Yale University in 1984, the fastest awarded Ph. D. at that institution. He was a senior scientist at the Max Planck Institute, working under the aegis of Nobel laureates Manfred Eigen and Robert Huber. Ariel Fernandez held faculty positions at Indiana University and Rice University, where he held the Karl F. Hasselmann chaired professorship in bioengineering until 2011. He has lately taken up entrepreneurial and research activities at his own pharmaceutical consultancy, Ariel Fernandez Innovation, and at Collegium Basilea, the Institute for Advanced Study in Basel, Switzerland.
Ariel Fernandez received various awards including the State of Buenos Aires medal to the best university graduate (1980), the Camille and Henry Dreyfus Distinguished New Faculty Award (1989), The Camille and Henry Dreyfus Teacher-Scholar Award (1991), the J. S. Guggenheim Memorial Foundation Fellowship (1995), the Alexander von Humboldt Award (1995), Eli Lilly Award (2004), Rice endowed chair professorship (2005), John and Ann Doerr Foundation Award (2006), etc. He was elected to the American Institute for Medical and Biological Engineering in 2006 and became an honorary member of Collegium Basilea, Switzerland.
Ariel Fernandez has lectured and published extensively in first-tier journals on a range of topics: algebra, dynamical systems theory, statistical mechanics, chemical physics, interfacial phenomena, drug design, cancer therapeutics and molecular evolution from a structural biology perspective. He is credited with 340 peer-reviewed scientific publications in prestigious venues such as Proceedings of the US National Academy of Sciences, Annual Reviews of Genetics, Nature, Physical Review Letters, Genome Research and others. Ariel Fernandez’s work has been reviewed in Nature, Nature Reviews Drug Design, Chemistry World (Royal Society), Scientific American, etc. Ariel Fernandez has also authored one book and two patents on drug therapy.
Some of Ariel Fernandez’s most celebrated contributions pertain to the field of drug design where his work can be described as translational. Using his physico-chemical insights, he introduced the concept of dehydron, a structural singularity in soluble proteins, and exploited this concept to construct a selectivity filter to design safer drugs. Thus, Ariel Fernandez championed the so-called wrapping technology in molecular engineering, and assessed the impact of these advances in the area of molecular cancer therapeutics. The wrapping technology enables the practitioner to design drugs with higher specificity than those currently available on the market by wrapping (i. e. shielding from water attack) the unique dehydron patterns of targeted proteins. The wrapping technology and its impact and ramifications for molecular therapeutics are described in Ariel Fernandez’s book: “Transformative Concepts for Drug Design: Target Wrapping”, Springer-Verlag, Berlin, 2010.
Drug discovery remains essentially an arcane field where trial and error and serendipity play a major role, while rational design is relegated to an ex-post-facto speculation. According to Ariel Fernandez’s perception, a paradigm shift is needed. In his book, Ariel Fernandez addresses these problems introducing novel theoretical tools from molecular biophysics than can revitalize drug discovery to match the daunting challenges of the post-genomic era. Thus, Ariel Fernandez’s dehydron physics is brought to fruition to design more efficacious and safer drugs. Details on these views and paradigm shift may be found in the Distinguished Scientific Leader lecture delivered by Ariel Fernandez at the Georgia Institute of Technology in 2010 (YouTube).
Representative publications by Ariel Fernandez:
Ariel Fernandez: “Self-Organization in the Center Manifold of Dissipative Systems”. Journal of Physics A, Letters. 21, L 295-L302 (1988).
Ariel Fernandez: “Random Energy Model for the Kinetics of RNA Folding.”
Physical Review Letters 65, 2259-2264 (1990).
Ariel Fernandez and Herschel Rabitz: “Localization of Strain in the RNA Backbone and its Functional Implication”. Physical Review Letters 69, 546-550 (1992).
Ariel Fernandez and Gustavo Appignanesi: “Variational Approach to Relaxation in Complex Free Energy Landscapes: The Polymer Folding Problem”. Physical Review Letters 78, 2668-2672 (1997).
Ariel Fernandez, Andres Colubri and R. Stephen Berry: “Topology to Geometry in protein folding: beta-lactoglobulin”. Proceeding of the National Academy of Sciences USA 97, 14062-14066 (2000).
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).
Ariel Fernández and Ridgway Scott: “Adherence of packing defects in soluble proteins.” Physical Review Letters 91, 018102 (2003).
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).
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).
Ariel Fernández: “Keeping Dry and Crossing Membranes.” Nature Biotechnology 22, 1081-1084 (2004).
Jianping Chen, Xi Zhang and Ariel Fernández: “Molecular basis for specificity in the druggable kinome: sequence-based analysis”. Bioinformatics 23, 563-572 (2007).
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).
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).
Ariel Fernández: “Molecular basis for evolving self-dissimilarity in the yeast protein interaction network”. PLoS Computational Biology 3, e226 (2007).
Han Liang, Kristina Rogale-Plazonic, Jianping Chen, Wen-Hsiung Li and
Ariel Fernández: “Protein under-wrapping causes dosage sensitivity and decreases gene duplicability”. PLoS Genetics 4, e11 (2008).
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).
Xi Zhang, Alejandro Crespo and Ariel Fernández: “Turning promiscuous kinase inhibitors into safer drugs”. Trends in Biotechnology 26, 295-301 (2008).
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).
Jianping Chen, Han Liang and Ariel Fernández: “Protein structure protection commits gene expression patterns”. Genome Biology 9, R107 (2008).
Ariel Fernández, Soledad Bazán and Jianping Chen: “Taming the induced folding of drug-targeted kinases”. Trends in Pharmacological Sciences 30, 66-71 (2009).
Ariel Fernández and Sean Sessel: “Selective antagonism of anticancer drugs for side-effect removal”. Trends in Pharmacological Sciences 30, 403-410 (2009).
Ariel Fernández and Jianping Chen: “Human capacitance to dosage imbalance: Coping with inefficient selection”. Genome Research 19, 2185-2192 (2009).
Ariel Fernández and R. Stephen Berry: “Golden rule for buttressing vulnerable soluble proteins”. Journal of Proteome Research (ACS) 9, 2643-2648 (2010).
Sean Sessel and Ariel Fernández: “Selectivity filters to edit out side effects in molecular anticancer therapy”. Current Topics in Medicinal Chemistry 11, 788-799 (2010).
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).
Ariel Fernández: “Nanoscale Thermodynamics of Biological Interfacial Tension”, Proceedings of The Royal Society A 467, 559-568 (2010).
Ariel Fernández: “Variational mechanics of water at biological interfaces”. Fast Track Communication. Journal of Physics A: Math. Theor. 44, 292001 (2011).
Ariel Fernández: “Biology avoids phase separations”. Journal of Physics A / Insights (2011) Online: http://iopscience.iop.org/1751-8121/labtalk-article/46468?labTalkTab
Ariel Fernández and Michael Lynch: “Nonadaptive origins of interactome complexity”. Nature 474, 502-505 (2011).
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).
Ariel Fernández: “Communication: Epistructural thermodynamics of soluble proteins”. Journal of Chemical Physics 136, 091101 (2012).
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)
Ariel Fernández: “Comunication: Nanoscale electrostatic theory of epistructural fields at the protein-water interface”. Journal of Chemical Physics 137, 231101 (2012).
Ariel Fernández Stigliano: “Breakdown of the Debye polarization ansatz at protein-water interfaces”. Journal of Chemical Physics 138, 225103 (2013).
Ariel Fernández: “Supramolecular evolution of protein organization”.
Annual Reviews of Genetics, in press (2014).
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).
Author: Ariel Fernández
Title: “Transformative Concepts for Drug Design: Target Wrapping”
Publisher: Springer, Heidelberg, Berlin
Publication year: 2010.
US 8,466,154 B2
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.