Applied Mathematics, Ariel Fernandez, Ariel Fernandez book, Ariel Fernandez Stigliano, Book review, 阿列尔·费尔南德斯, Protein Biophysics, Ridgway Scott

Book Review on “A Mathematical Approach to Protein Biophysics” by Ridgway Scott and Ariel Fernandez: An Introduction to AF’s Solution to the Protein Folding Problem

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 Ridgway Scott and Ariel 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



AAAS, Argentina, Ariel Fernandez, Ariel Fernandez Research, Ariel Fernandez Stigliano, Clare Francis, Corruption, 阿列尔·费尔南德斯, Hasselmann Professor at Rice University, Marcia McNutt, Research Integrity, Retraction Watch, Rice University, Science, Science Magazine, Science reproducibility, Science Transparency, Scientific corruption, Scientific Integrity, Scientific Reproducibility, Scientific Research, Weishi Meng on Ariel Fernandez

On “Promoting an Open Research Culture”, Policy Forum, Science Magazine

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. In this regard, this is what Science Transparency has to say:

There is a perceived or real crisis over the reproducibility and transparency of scientific reporting. This crisis is surely being mismanaged by scientists, and they have only themselves to blame. Scientific pursuit requires a highly specialized training, and consequently, so does the assessment of the validity of reported science. Yet, while scientists figure out how to deal with the current crisis, they are allowing journalists like Ivan Oransky (named Science’s Garbage Man by the Swiss Radio and Television), defamation rings, and anonymous nobodies to tell them what to do. This is especially apparent in certain journals that keep listening to Clare Francis, Retraction Watchers or some of the pubpeers, who are in fact nobody’s peers. This nonsense where anyone says whatever they want and pours their anger on the internet, only fuels the current hysteria over fake science. More on this problem has been previously covered in Science Transparency.

As usual, Prof. Ariel Fernandez (阿列尔·费尔南德斯), the discoverer of the dehydron (脱水元), is on the mark in regards to this issue, and his pronouncement featured in Science is reproduced below in accord with Terms and Conditions on User Submissions to Science.


Dr. Ariel Fernandez

Dr. Ariel Fernandez . 阿列尔·费尔南德斯

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 (Follow Ariel Fernandez on Twitter).

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。


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]




阿列尔·费尔南德斯 – Ariel Fernandez biosketch at Baidu Baike

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: