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Ariel Fernandez’s Alternative “WaterMaps” of 2007 Look Much Like Precursors to WaterMap

Ariel Fernandez   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 as now described by Ariel Fernandez and Ridgway Scott in Trends in Biotechnology (2017) 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.  And here is a “WaterMap” by Ariel Fernandez, dating back to 2007, used exactly as WaterMap is used:

WaterMap by Ariel Fernandez (J. Clin. Invest., 2007)

“WaterMap” by Ariel Fernandez dating back to 2007 (The Journal of Clinical Investigation 117, 4044-4054, 2007, reproduced with permission).

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”.


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Book Review: “Physics at the Biomolecular Interface” by Ariel Fernandez

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.

Ariel Fernandez 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.

Dr. Ariel Fernandez, 2016

Dr. Ariel Fernandez, 2016

Some highlights of the book certainly worth mentioning are:

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.

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.


ORCID Record for Ariel Fernandez

Selected publications of Ariel Fernandez

Argentina, Ariel Fernandez, Ariel Fernandez Patent, Ariel Fernandez Stigliano, Biotechnology, Converging Technologies, Dehydron, 阿列尔·费尔南德斯, National Science Foundation, NSF, ProWDSciences, Sangtae Kim, Weishi Meng on Ariel Fernandez

Converging Technologies at ProWDSciences: Protein-Water-Dehydron-Bingo!

Translational research involving converging technologies is clearly the way of the future for drug discovery and the pharmaceutical industry. At least, this is what we are being told by leading scientist Sangtae Kim in a recent NSF lecture on Converging Technologies. The great Sangtae Kim himself appears to have followed this mantra when he founded the biotech company ProWDSciences, where “ProWD” stands for Protein-Water-Dehydron. As the name informs us, ProWD Sciences is all about converging technologies. The idea is enshrined in the unfamiliar word dehydron (脱水元). Dehydron is the central concept of epistructural biology, a new scientific field developed by Ariel Fernandez to deal with the complex physics of the protein-water interface. To properly define dehydrons, a multiscale theory of biological water may be required, as Kim would say. Yet, as described in the book Biomolecular Interfaces, we may say that dehydrons refer to structural deficiencies in proteins that promote interfacial tension, are endowed with catalytic properties and serve as selectivity filters for drug design.  As the research of Ariel Fernandez suggests, the dehydron may well be the point of convergence of nanotechnology, biotechnology, molecular engineering and learning technologies, the sort of convergence that Kim described in his NSF lecture. Time will tell us how this technological convergence will enable the rational design of safer anticancer drugs with optimal selectivity control.

Ariel Fernandez and Sangtae Kim

Ariel Fernandez (left) and Sangtae Kim toying with a dehydron-based molecular design at the Morgridge Institute for Research (University of Wisconsin-Madison)

Argentina, Ariel Fernandez, Ariel Fernandez book, Ariel Fernandez Nature paper, Ariel Fernandez Publications, Ariel Fernandez Research, Ariel Fernandez Stigliano, Baidu, Baidu Encyclopedia, Biochemical Reaction, Biochemistry, Biotechnology, Buenos Aires, Dehydron, Enzyme Catalysis, 阿列尔·费尔南德斯, Hasselmann Professor at Rice University, Oktay Sinanoglu, Republic of China, Rice University, Richard Moss, Scientific Research, Weishi Meng on Ariel Fernandez, Yale University

Ariel Fernandez at the Center of a Transformative Biotechnology



Ariel Fernandez (阿列尔·费尔南德斯, also styled as Ariel Fernandez Stigliano, CV linked and updated 5/18/2015) 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 (see Ariel Fernandez’ PhD Tree). Ariel Fernandez became widely known as the discoverer of the dehydron (脱水元) at the turn of the 21st century. His recent publications, and especially his latest book “Biomolecular Interfaces: Interactions, Functions and Drug Design” (ISBN 978-3319168494, Springer, available at Amazon), place him at the center of a veritable biotechnological transformation. We may term this transformation “dehydronic chemistry” because it explores the technological implications of the newly discovered chemical/catalytic role of dehydrons. 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 (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)


Book flyer

Protein dehydrons have an established role as promoters of protein associations because they create poor interfaces with water. Biologists have become acquainted with this role of dehydrons ever since Ariel Fernandez’ Nature paper decisively revealed the importance of dehydrons in establishing the nonadaptive origin of interactome complexity. This crucial discovery was reviewed at Nature by science writer Philip Ball.

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, Ariel Fernandez and the eminent cardiologist Richard L. Moss invented a drug-based treatment for heart failure.

Invention by Richard Moss and Ariel Fernandez to treat heart failure. Patent US9,051,387 awarded June 9, 2015

Invention by Richard Moss and Ariel Fernandez to treat heart failure. Patent US9,051,387 awarded June 9, 2015

This US patent number 9051387 describes the first therapeutic disruption of a protein-protein association using a man-made ligand, a challenge considered the holy grail in drug discovery. You may find this invention at: US Patent and Trademark Office page, Espacenet page, Description by the University of Wisconsin-Madison, Ariel Fernandez Consultancy,, Ariel Fernandez’s professional page.

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

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 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 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 (see also Ariel Fernandez’s blog).

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 (see Ariel Fernandez’ PhD Tree), a peerless genius who recently passed away. Oktay Sinanoglu became the youngest full professor at Yale in its modern history, I believe.


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

Oktay Sinanoglu with Linus Pauling

Oktay Sinanoglu with Linus Pauling

Oktay Sinanoglu with Ariel Fernandez

Oktay Sinanoglu with Ariel Fernandez, Cape Cod, 1984

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.


Books on Biological Matter Physics by Ariel Fernandez

Description of latest book by Ariel Fernandez

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

Biomolecular Interfaces: The latest book chapter by chapter

Ariel Fernandez Wikipedia (Mandarin)

Ariel Fernandez Wikipedia (Spanish)

Ariel Fernandez Wikipedia (English)

Ariel Fernandez, Editor for Metabolomics (profile)

Follow Ariel Fernandez on Twitter

Biomedical Research by Ariel Fernandez as Listed in PubMed, NCBI / NIH





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: