The shaping of a molecular linguist: How a career studying DNA energetics revealed the language of molecular communication
2021; Elsevier BV; Volume: 296; Linguagem: Inglês
10.1016/j.jbc.2021.100522
ISSN1083-351X
Autores Tópico(s)Gene Regulatory Network Analysis
ResumoMy personal and professional journeys have been far from predictable based on my early childhood. Owing to a range of serendipitous influences, I miraculously transitioned from a rebellious, apathetic teenage street urchin who did poorly in school to a highly motivated, disciplined, and ambitious academic honors student. I was the proverbial "late bloomer." Ultimately, I earned my PhD in biophysical chemistry at Yale, followed by a postdoc fellowship at Berkeley. These two meccas of thermodynamics, coupled with my deep fascination with biology, instilled in me a passion to pursue an academic career focused on mapping the energy landscapes of biological systems. I viewed differential energetics as the language of molecular communication that would dictate and control biological structures, as well as modulate the modes of action associated with biological functions. I wanted to be a "molecular linguist." For the next 50 years, my group and I used a combination of spectroscopic and calorimetric techniques to characterize the energy profiles of the polymorphic conformational space of DNA molecules, their differential ligand-binding properties, and the energy landscapes associated with mutagenic DNA damage recognition, repair, and replication. As elaborated below, the resultant energy databases have enabled the development of quantitative molecular biology through the rational design of primers, probes, and arrays for diagnostic, therapeutic, and molecular-profiling protocols, which collectively have contributed to a myriad of biomedical assays. Such profiling is further justified by yielding unique energy-based insights that complement and expand elegant, structure-based understandings of biological processes. My personal and professional journeys have been far from predictable based on my early childhood. Owing to a range of serendipitous influences, I miraculously transitioned from a rebellious, apathetic teenage street urchin who did poorly in school to a highly motivated, disciplined, and ambitious academic honors student. I was the proverbial "late bloomer." Ultimately, I earned my PhD in biophysical chemistry at Yale, followed by a postdoc fellowship at Berkeley. These two meccas of thermodynamics, coupled with my deep fascination with biology, instilled in me a passion to pursue an academic career focused on mapping the energy landscapes of biological systems. I viewed differential energetics as the language of molecular communication that would dictate and control biological structures, as well as modulate the modes of action associated with biological functions. I wanted to be a "molecular linguist." For the next 50 years, my group and I used a combination of spectroscopic and calorimetric techniques to characterize the energy profiles of the polymorphic conformational space of DNA molecules, their differential ligand-binding properties, and the energy landscapes associated with mutagenic DNA damage recognition, repair, and replication. As elaborated below, the resultant energy databases have enabled the development of quantitative molecular biology through the rational design of primers, probes, and arrays for diagnostic, therapeutic, and molecular-profiling protocols, which collectively have contributed to a myriad of biomedical assays. Such profiling is further justified by yielding unique energy-based insights that complement and expand elegant, structure-based understandings of biological processes. I was born in Jönköping, Sweden, the third child of parents who were refugees from Nazi Germany and who eventually settled in New York City. My mother was a Columbia University–trained social worker who always provided me with gentle nurturing and encouragement. My father was a frustrated academician who became a businessman in New York. In stark contrast with my mother, my father was strict and demanding. Much to my father's delight, my older sister and brother both were academic superstars. By contrast, much to my father's consternation, I was a "street urchin" who was far more interested in sports than academics. I was "saved" by my high school baseball coach, Dr Edson Scudder, a Princeton PhD, who taught history. He told me that unless I improved my grades, he would not allow me on the baseball team. Each day, Dr Scudder would stay after school and tutor me. My grades soared, as I became the only person in the high school to go in one semester from academic probation to the academic honor roll! For the rest of my high school years, I started in left field and won all-conference honors. Despite my relatively weak arm, I was a very good hitter. I went on to college and majored in history because of Dr Scudder's influence. I also majored in chemistry because I wanted eventually to become employed. I believe I was the only such double major that year at the university. From these somewhat uneven beginnings, I never could have envisioned a day when I would write a Reflections piece of my nearly 5 decades of DNA scientific research. My personal story proves that, in the race of life, not all winners take the lead immediately out of the starting gate. I am convinced this is why I never give up on any of my students, knowing that they also may prove to be late bloomers. I am humbled and honored to be able to share with you my personal and professional reflections. As a teenager growing up in New York City, I had three passions: baseball, history, and science. Brief stints playing college and minor league baseball convinced me to focus my attention on the other two passions. As noted above, I earned a BA in history and a B.S. in chemistry from the University of Wisconsin at Madison, graduating in 1968. The Vietnam War and the associated draft sharply shaped the next prioritization of my career. Science would become my vocation, and history would be my avocation, as they both remain so to this day. In graduate school at Yale, I began as a physical organic chemist. Under the mentorship of Professor Jerome A. Berson, I investigated terpene rearrangements. The goal was to test the limits of the orbital symmetry properties that formed the underpinnings of the Nobel Prize–winning Woodward–Hoffmann rules. At the same time, I took an elective course in physical biochemistry, taught by Joe Fruton and Fred Richards. This course had a profound impact on my scientific trajectory. I was fascinated to learn how the three-dimensional shapes and functions of large, complex biological compounds, including polymers, could be understood in terms of fundamental thermodynamic and kinetic properties. The lecturers frequently underscored that all biochemical events are controlled and regulated by differential energetics, which are manifest in maps of the isolated and interacting energy landscapes. In essence, favorable and unfavorable interaction energies constitute the words of the molecular language by which molecules communicate and orchestrate their structures, stabilities, and functions, or dysfunctions. I was smitten! I went on to pursue my PhD studies in biothermodynamics and kinetics at Yale University with Julian Sturtevant (1Breslauer K.J. Julian Sturtevant: Scientific giant, warm humanist, social activist, nature lover, gentle teacher, kind friend.Biophys. Chem. 2007; 126: 9-10Crossref PubMed Scopus (0) Google Scholar), followed by a postdoc at the University of California, Berkeley, with Ignacio "Nacho" Tinoco Jr. (2Tinoco I. Fun and games in Berkeley: The early years (1956–2013).Annu. Rev. Biophys. 2014; 43: 1-17Crossref PubMed Scopus (0) Google Scholar), and finally, in 1974, a faculty position at Rutgers University, where I remain to this day. During my first 5 or 6 years at Rutgers, I split my time between intramural softball with the students and setting up my laboratory, where I conducted research in pursuit of nature's secrets of life, as well as in pursuit of tenure! I have been at Rutgers for 47 years, during which I became a husband, a father, the Linus C. Pauling distinguished university professor, the founding dean of the Division of Life Sciences, and vice president for health science partnerships. Currently enabled by an outstanding group of colleagues in my laboratory, I continue my biophysical research programs, which collectively focus on characterizing the forces that modulate the regulation and dysregulation of biological processes crucial to human health. My laboratory at Rutgers has spent nearly 5 decades creating DNA databases that systematically characterize the intramolecular and intermolecular forces, which collectively constitute the words, sentences, paragraphs, and chapters in the book of molecular communication. As such, one could reasonably characterize me as a molecular linguist. This scientific focus was shaped within me by my early training at Yale from 1968 to 1972. Julian Sturtevant (1Breslauer K.J. Julian Sturtevant: Scientific giant, warm humanist, social activist, nature lover, gentle teacher, kind friend.Biophys. Chem. 2007; 126: 9-10Crossref PubMed Scopus (0) Google Scholar) and Donald Crothers (3Tinoco Jr., I. The ethical scientist: An old-fashioned view.Biopolymers. 2015; 103: 424-431Crossref PubMed Scopus (0) Google Scholar) unrelentingly emphasized to me, and others, the importance of quantitatively characterizing the energy profiles of molecular assemblies to understand the origins of the structures, as well as the modes of action of their functions. I was surprised by how quickly I became a convert to their mantras because as a student I observed that no single word in the scientific lexicon could more rapidly empty a classroom than "thermodynamics." However, conversations and classes with them, as well as with Lars Onsager, Oktay Sinanoğlu, Kenneth Wiberg, and others, made energetic profiling my passion rather than my fear. My conversion was further facilitated by Don Crothers asking me to proofread and propose edits for a textbook manuscript that he, Ignacio Tinoco, and Victor Bloomfield were writing (4Bloomfield V.A. Victor B. Crothers D.M. Tinoco I. Crothers D. Physical Chemistry of Nucleic Acids. Harper & Row, New York, NY1974Google Scholar). I was mesmerized by the quantitative rigor and clarity of explanations presented in the text, and I felt privileged to have such a sneak peek before publication. This opportunity was coupled with the 1973 publication of the Tinoco/Crothers landmark paper "Improved Estimation of Secondary Structure in Ribonucleic Acids" (5Tinoco Jr., I. Borer P.N. Dengler B. Levine M.D. Uhlenbeck O.C. Crothers D.M. Gralla J. Improved estimation of secondary structure in ribonucleic acids.Nat. New Biol. 1973; 246: 40-41Crossref PubMed Google Scholar), and I became even more convinced of the need for further energy studies on biological systems. In 1973, Douglas Turner and I were postdocs in the Tinoco laboratory, during which time we became close friends; although I still cannot get over the fact that he bested me 1-0 in a game of stickball! It is interesting to note that when we accepted independent faculty appointments, Doug built his stellar academic career on an impressive and much-needed elaboration of RNA energy profiling (referred to as the "Turner Numbers") (6Turner D.H. Sugimoto N. Freier S.M. RNA structure prediction.Annu. Rev. Biophys. Biophys. Chem. 1988; 17: 167-192Crossref PubMed Google Scholar), while my academic career has focused on establishing DNA energy databases, including their drug- and protein-binding properties. My choice of research programs as well as my deep commitment to data collection were profoundly influenced by my years in Sturtevant's laboratory at Yale (1Breslauer K.J. Julian Sturtevant: Scientific giant, warm humanist, social activist, nature lover, gentle teacher, kind friend.Biophys. Chem. 2007; 126: 9-10Crossref PubMed Scopus (0) Google Scholar). I fondly recall a conversation with Julian in which I showed him my voluminous tabulation of calorimetric data on a biological system and lamented that I could not discern any pattern that would glean new insights. He gently smiled and said, "That only means you haven't yet collected enough data, since the patterns will become self-evident when you reach the critical data density." From that moment forward, I committed myself to a career of databasing, of ever-increasing density, on biologically relevant molecules. It therefore should come as no surprise that as a dean and vice president, I recruited Helen Berman, who established at Rutgers the international structural database (Research Collaboratory for Structural Bioinformatics Protein Data Bank, or RCSB EDB) (7Berman H.M. Burley S.K. Kleywegt G.J. Markley J.L. Nakamura H. Velankar S. The archiving and dissemination of biological structure data.Curr. Opin. Struct. Biol. 2016; 40: 17-22Crossref PubMed Scopus (21) Google Scholar, 8Young J.Y. Westbrook J.D. Feng Z. Peisach E. Persikova I. Sala R. Sen S. Berrisford J.M. Swaminathan G.J. Oldfield T.J. Gutmanas A. Igarashi R. Armstrong D.R. Baskaran K. Chen L. et al.Worldwide Protein Data Bank biocuration supporting open access to high-quality 3D structural biology data.Database (Oxford). 2018; 2018bay002Crossref Scopus (24) Google Scholar) and subsequently recruited her successor, Stephen Burley, as the director (9Burley S.K. Berman H.M. Bhikadiya C. Bi C. Chen L. Di Costanzo L. Christie C. Dalenberg K. Duarte J.M. Dutta S. Feng Z. Ghosh S. Goodsell D.S. Green R.K. Guranovic V. et al.RCSB protein Data Bank: Biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy.Nucleic Acids Res. 2019; 47: D464-D474Crossref PubMed Scopus (403) Google Scholar). During my early years, in the mid-1970s to early 1980s, I also was influenced by the published works of and conversations with Walter Kauzmann, Rufus Lumry, Peter Privalov, Harold Scheraga, Charles Tanford, and other luminaries. These interactions further convinced me of the importance of an energy database focus for my own research. While Tinoco, Crothers, Turner, and others focused on RNA energetics, I decided that direct, model-independent, calorimetric characterizations of DNA energetics was needed. My postdoc project, published in the Journal of Molecular Biology in 1975 (10Breslauer K.J. Sturtevant J.M. Tinoco Jr., I. Calorimetric and spectroscopic investigation of the helix-to-coil transition of a ribo-oligonucleotide: rA7U7.J. Mol. Biol. 1975; 99: 549-565Crossref PubMed Google Scholar), introduced the Tinoco group to the added insights derived from a differential scanning calorimetric mapping of the energetics of an oligomeric ribo duplex. Based on this demonstration, coupled with improvements in DNA synthesis and commercially available, high-sensitivity calorimeters, Tinoco, Crothers, and Sturtevant encouraged me initially to focus my own laboratory work on DNA energetics, as elaborated below. During my first decade at Rutgers (1974–1984), I pursued a range of calorimetric studies on specially designed and synthesized DNA oligomers of systematically varying sequences. From these measurements, and inspired by the work of Tinoco and Crothers (5Tinoco Jr., I. Borer P.N. Dengler B. Levine M.D. Uhlenbeck O.C. Crothers D.M. Gralla J. Improved estimation of secondary structure in ribonucleic acids.Nat. New Biol. 1973; 246: 40-41Crossref PubMed Google Scholar, 11Aboul-ela F. Koh D. Tinoco Jr., I. Martin F.H. Base-base mismatches. Thermodynamics of double helix formation for dCA3XA3G + dCT3YT3G (X, Y = A,C,G,D).Nucleic Acids Res. 1985; 13: 4811-4824Crossref PubMed Scopus (0) Google Scholar, 12Gralla J. Crothers D.M. Free energy of imperfect nucleic acid helices.J. Mol. Biol. 1973; 78: 301-319Crossref PubMed Scopus (0) Google Scholar), I was able to derive the first direct, model-independent, calorimetrically derived DNA thermodynamic library of sequence-dependent, nearest-neighbor interactions (13Breslauer K.J. Frank R. Blocker H. Marky L.A. Predicting DNA duplex stability from the base sequence.Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 3746-3750Crossref PubMed Google Scholar)—a library that quickly became used throughout molecular biology to rationally design DNA primers and probes. During my second decade and a half at Rutgers (1984–2000), my laboratory increased the data density of this DNA library to include many noncanonical, biologically relevant altered features of DNA forms, such as triplexes, tetraplexes, bent DNA, crosslinked DNA structures, ligand-perturbed DNA structures, and drug-bound structures. Overlapping this period up to the present, we have focused on mapping the rough energy landscapes of metastable DNA states, as well as characterizing lesion-induced alterations in DNA properties and how these perturbations correlate with biological recognition, processing, repair, mutagenesis, cytotoxicity, and other biologically relevant properties. In my filing cabinet at Rutgers is an artifact reflecting my laboratory's growing recognition in biothermodynamics. The folder is titled Kauzmann v. Lumry. They were very close friends; in fact, Rufus was Walter's best man at his wedding. However, their friendship was tested in the late 1970s, as they exchanged heated arguments about thermodynamics. They finally asked me to serve as an intermediary for their correspondence to avoid making their letters too abrasive. I was both honored and intimidated. I refrain from sharing further substance of this file, given my deep respect for both individuals and my confidential role as an impartial arbitrator! I will say, however, the experience validated me in the eyes of two giants in the field, further cementing my confidence to pursue a career dedicated to mapping the energetics of biological systems. In this reminiscing Reflections article, I provide select examples of how, starting in 1974, my laboratory at Rutgers, and, previously and/or contemporaneously, the laboratories of others (e.g., Ignacio Tinoco, Don Crothers, Victor Bloomfield, Peter von Hippel, David Mathews, Doug Turner) were demonstrating that nucleic acid energy profiles, both thermodynamic and kinetic, provide the missing links between DNA and/or RNA biological structures, differential stabilities, and biological functions. The experimental and computational mapping of energy profiles that bridge the conceptual and practical gaps between biopolymer structures and biological functions is motivating a generation of young scientists to pursue bioenergetic studies. As elaborated in this article, such profiling is justified by yielding unique energy-based insights that complement and expand elegant, structure-based understandings of biological processes. Enhanced reporting of energy profiling, both thermodynamic and kinetic, reflects the expanding recognition that such fundamental data are essential for foundational understandings of molecular recognition, as well as for the establishment of new biomedically relevant applications. In fact, DNA energy databases have enabled a revolution in quantitative molecular biology through the rational design of primers, probes, and arrays for diagnostic, therapeutic, and molecular-profiling protocols that have contributed to a myriad of biomedical assays. The future is bright for those physical, computational, and structural chemists who also choose to focus on characterizing the energy landscapes of complex biological assemblies. As noted above, energetics provides the bridge between biological structure and biochemical function. International genomics and proteomics initiatives, empowered by technological and methodological advances, have produced a wealth of crucial structural and functional data (7Berman H.M. Burley S.K. Kleywegt G.J. Markley J.L. Nakamura H. Velankar S. The archiving and dissemination of biological structure data.Curr. Opin. Struct. Biol. 2016; 40: 17-22Crossref PubMed Scopus (21) Google Scholar, 9Burley S.K. Berman H.M. Bhikadiya C. Bi C. Chen L. Di Costanzo L. Christie C. Dalenberg K. Duarte J.M. Dutta S. Feng Z. Ghosh S. Goodsell D.S. Green R.K. Guranovic V. et al.RCSB protein Data Bank: Biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy.Nucleic Acids Res. 2019; 47: D464-D474Crossref PubMed Scopus (403) Google Scholar, 14Goodsell D.S. Burley S.K. Berman H.M. Revealing structural views of biology.Biopolymers. 2013; 99: 817-824Crossref PubMed Scopus (4) Google Scholar). In contrast, the mapping of the energy landscapes that link these structures with their biological functions has lagged. This deficiency is manifest in and inhibitory of numerous biomedical research efforts, including, but not limited to, energy-based drug design (EBDD), hybridization-based gene regulation, mechanisms of DNA repair, differential protein stabilities and their folding/misfolding pathways, rational protein engineering, and many other examples. This article is not intended to discuss all such areas but rather to select several DNA systems that exemplify the value of energetics as the essential link between biological structure and function. To this end, this article primarily will use DNA examples from my own laboratory, while acknowledging that many other laboratories have made important contributions to building such energy bridges, both computationally and experimentally, for other biological systems. Over the years, my laboratory's studies have been greatly influenced and enriched by interactions with visiting luminaries, as part of distinguished lecture series, as well as by national and international collaborations with visiting scientists on sabbatical, followed by the hiring of some of their best students. To be specific, in the late 1960s to early 1970s, the Peruvian government sent some of their best young scientists to the United States for training. I was fortunate enough to have one, Dr Luis Marky, join my group and take the lead on several projects, including calorimetric determination of our original, nearest-neighbor DNA database compilation. True to the collaborative nature of my group, we were able to achieve the requisite data density and diversity for these studies by studying specially designed oligomeric and polymeric DNA samples produced and provided by a German research team led by Helmut Blöcker and Ronald Frank. Clearly, it took an international scientific village to produce the first calorimetrically determined, nearest-neighbor DNA database (13Breslauer K.J. Frank R. Blocker H. Marky L.A. Predicting DNA duplex stability from the base sequence.Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 3746-3750Crossref PubMed Google Scholar). In this same collaborative spirit of science without borders, we pursued additional energy profiling, including drug–DNA mapping, empowered by cooperative, sabbatical-based joint ventures with Slovenian scientists, Professors Gorazd Vesnaver and Ciril Pohar, as well as Natasa Poklar, all from the University of Ljubljana; with Czech Republic scientists, Professors Bohdan Schneider and Ctirad Hofr; with German and South African scientists, Professors Horst Klump and Jens Völker; with Armenian and Russian scientists (from the former Union of Soviet Socialist Republics), Professors Armen Sarvazyan, Tigran Chalikian, and Vera Gindikin; with Chinese scientists, Dr Renzhe Jin (a Tiananmen Square refugee) and Wan-Yin Chou; with a South Korean scientist, Dr Young-Whan Park; with Polish scientists, Dr Danuta Szwajkajzer and Slawomir S. Mielewczyk; with a Brazilian scientist, Professor Cica Minetti; as well as with United States–based scientists, including Drs. Eric Plum, Craig Gelfand, William Braunlin, and Scott Law and Professors David Remeta, Dorothy Erie, Arthur Grollman, Francis Johnson, Dani Pilch, Ron Breslow, Peter Dervan, Roger Jones, Barbara Gaffney, Gary Glick, Nick Geacintov, Doug Turner, Jerry Manning, Wilma Olson, and many others. One of the goals of this article is to illustrate selectively the need for fundamental thermodynamic measurements on complex DNA systems, while also acknowledging the significance of kinetic factors that further shape energy landscapes; particularly, as manifest in suboptimal, metastable states that can serve as regulatory switches, a feature reflected in the work of Jens Völker, who is now a research professor in my group at Rutgers. In short, DNA energy profiling enables the establishment of essential linkages between high-profile DNA structures and crucial biological functions/pathways. By underscoring the enhanced insights derived from such DNA energy mapping, a generation of classically trained physical chemists may be motivated to apply their invaluable expertise to clarify the complexities of biological systems in terms of fundamental physiochemical principles. In so doing, they would greatly enrich the scientific arsenal of the biophysical community. My introduction to calorimetric instrumentation was less than encouraging; in fact, it bordered on the traumatic, as I explained in a published tribute to the memory of Julian Sturtevant (1Breslauer K.J. Julian Sturtevant: Scientific giant, warm humanist, social activist, nature lover, gentle teacher, kind friend.Biophys. Chem. 2007; 126: 9-10Crossref PubMed Scopus (0) Google Scholar). It was late 1968/early 1969, and I was beginning my PhD studies at Yale in the Sturtevant laboratory. One evening, during my first few months there, I detected some erratic behavior by the flow calorimeter. As I wrote in the tribute to Julian (1Breslauer K.J. Julian Sturtevant: Scientific giant, warm humanist, social activist, nature lover, gentle teacher, kind friend.Biophys. Chem. 2007; 126: 9-10Crossref PubMed Scopus (0) Google Scholar):It appeared that some moisture had breached the sealed submarine in which the heat sink and flow tubing were embedded. With some trepidation, I called Julian at his home, anticipating that he would tell me to stop and that he would look at it in the morning. Instead, Julian directed me to dissemble the instrument, place the heat sink in a drying oven, and then reassemble the unit in the morning. I politely listened, but I was terrorized by this directive, having never even seen the immersed calorimeter beyond the motor-driven syringes I used to deliver the reactant solutions. When I shared my fear with Dr Sturtevant, he chuckled and said 'You should know what the insides of the instrument looks like and how it works. Only then will you understand what you really are measuring so you can interpret your data and design new experiments in an informed manner.' I proceeded to dissemble the instrument, with the screwdriver shaking in my hand. I finally got to the heat sink, disconnected the flow tubing, and I placed the aluminum block in the drying oven. I then returned to my desk to enter all this information into my laboratory notebook. An hour later, I opened the drying oven and looked inside the heat sink. To my amazement and terror, I saw a pool of a reflective, silvery liquid that looked like melted metal. Had I just destroyed the instrument by melting the flow tubing? My terror prevented me from realizing that the temperature of the gentle drying oven was very far below the melting point of platinum or any other material used for construction of the instrument. I decided that I had to call and tell Dr Sturtevant what transpired, despite fearfully envisioning next day headlines proclaiming the shortest tenure of a graduate student in the history of Yale University. When I apologetically confessed to Dr Sturtevant what had happened, he roared with laughter and told me that the melted material was just 'woods metal' used to enhance thermal contact and that everything was fine. I instantly became a Julian Sturtevant fan for life. Given this maiden voyage with calorimetric instrumentation, it is a true testament to Julian's sensitivity and humanity that I have made this class of instruments the cornerstone of my research career. It has been long recognized that calorimetry represents the most direct, model- and label-free experimental approach for obtaining the energy data of interest. However, for decades, most commercially available calorimeters lacked the sensitivity required for detecting the small amount of heat accompanying biological studies. A few laboratories, most notably those of Julian Sturtevant, Peter Privalov, Rufus Lumry, and later John Brandts and Rod Biltonen built one-off, more sensitive microcalorimeters to conduct their biothermodynamic measurements, yet these instruments initially were not commercially available, and they lacked the throughput desired for many applications. Motivated by these limitations, specialty companies such as MicroCal, Calorimetry Sciences Corp., Tronac, Malvern Panalytical, and Thermal Analysis began to commercialize highly sensitive microcalorimeters, thereby enabling an increasing number of laboratories capable of performing bio-level measurements. The next technical hurdle was to increase throughput, a challenge that has been surmounted via automation and multicell configurations, thereby making the methodology far more appealing to drug discovery/material science screening efforts. Armed with this new generation of microcalorimeters, one now has the ability to map the subtleties of energy landscapes, including metastable states and conformational switches that are at the foundation of regulatory events in biology and thus are essential for the rational design of physiochemical properties in material sciences. Physical chemists know that energetics represent the universal language of molecular recognition. Likewise, biophysical chemists know that energetics are required to bridge the conceptual and practical gaps between structure and function. Through the ongoing efforts of both overlapping communities, energy databases are beginning to become sufficiently populated to allow for fundam
Referência(s)