The shaping of a molecular linguist: How a career studying DNA energetics revealed the language of molecular communication

Abstract

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.

Political science meets physical science: The shared concept of stability

“…Analogous “thermodynamic selection” arguments have been posited by Breslauer ( 32 ) for energy-based drug design, and, as noted above, by Horst Klump, Jens Volker, and Ken Breslauer ( 18 ) to yield an energy-based, reductionist explanation for the molecular complexity associated with the evolution of the genetic code, as well as with the genotypic stability concept of “molecular Darwinism,” as an adjunct to Darwin's “survival of the fitness” phenotypic arguments.…”

Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization

“…During the past four decades, Professor Breslauer and his colleagues have focused their attention on timely topics of biological relevance by conducting biophysical research studies that assisted parallel biomedical efforts to identify effective treatment strategies for a number of devastating diseases. Such efforts have culminated in characterizing the energetics of drug-DNA interactions, particularly those directed towards the treatment of cancer and related ailments [14][15][16][17][18][19], revealing insightful trends in terms of thermodynamic binding signatures [18][19][20][21][22] and yielding invaluable information content for advancing drug discovery strategies [23][24][25]. In a series of seminal studies, Professor Breslauer established a database of nearest neighbor thermodynamics for canonical DNA duplexes [26], advanced the concept of enthalpy-entropy compensation in ligand-target interactions [15] which represents a formidable challenge in drug design efforts, explored the relevance of heat capacity changes on DNA duplex energetics [27,28] and macromolecular processes [29], and characterized the thermodynamics of template-directed polymerase synthesis [30].…”

“…In collaboration with Professors Grollman and Johnson at Stony Brook University, the Breslauer research group has investigated oxidative DNA damage, which causes a myriad of diseases including cancer and neurodegeneration. These efforts have complemented biophysical studies of canonical DNA with detailed thermodynamic analysis of lesion impacts on duplex energetics [31][32][33][34][35][36][37][38][39][40][41][42] as well as lesion recognition and repair by DNA glycosylases [23,29,43,44]. While establishing the foundation required for understanding the energetic basis of complex biological systems, the Breslauer research group has focused on gene transcription regulation, repair, and replication [29,30,39,45,46].…”

“…While establishing the foundation required for understanding the energetic basis of complex biological systems, the Breslauer research group has focused on gene transcription regulation, repair, and replication [29,30,39,45,46]. Professor Breslauer's impressive academic career spanning five decades is chronicled in a recent retrospective [23] as his research group continues to pursue effective therapeutic interventions for combating and treating infectious diseases such as the SAR-CoV-2 pandemic [47]. In summary, the indelible impact of Professor Breslauer's pioneering contributions to the field of biothermodynamics and their consequential impact on advancing drug discovery strategies is gratefully acknowledged and recognized by a legion of peers.…”

Characterization of Aurintricarboxylic Acid (ATA) Interactions with Plasma Transporter Protein and SARS-CoV-2 Viral Targets: Correlation of Functional Activity and Binding Energetics

“…Over the past several decades, the Breslauer, Grollman, and Johnson research laboratories have pursued a collaborative synergistic program to elucidate specific structure-function-energetic correlations in systems of biomedical relevance. This comprehensive multiparametric strategy has enabled us to characterize the overall impact of carcinogenic and mutagenic DNA lesions [1][2][3][4][5][6][7][8][9] on nucleic acid recognition [10], replication [11], and repair [10,12] (as reviewed in [13]). Applying the methodology developed and Life 2022, 12, 872 2 of 28 refined during this timeframe towards identifying effective treatment protocols to combat infectious diseases, our laboratories are currently exploring investigational compounds and repurposed molecules to assess their overall therapeutic potential as anti-SARS-CoV-2 inhibitors.…”