Career accomplishments of Harold A. Scheraga.

H Scheraga has been a pioneer in the application of physical chemical methods to biological systems. Remarkably, his research program has spanned over six decades and is still going strong. His entire academic career has been at Cornell University where he received his initial academic appointment in 1947. He has combined both experimental and theoretical approaches to produce a new understanding of molecular interactions within and between proteins. In addition, he has been an exceptional mentor of young scientists both within his research program and in the classroom. He has also been an exemplary citizen of the university and scientific community, having served as Chair of the Department of Chemistry and on study sections and other review committees. What follows is a brief summary of Harold’s many accomplishments. His career has also been highlighted in a recent Annual Review of Biophysics (40, 1−39 (2011)). When Harold joined the chemistry faculty at Cornell University, protein biophysics was in its infancy; much of the knowledge and understanding we take for granted today was unknown. Proteins had not been sequenced, nor was there a detailed understanding of the three-dimensional structures and functions of DNA and proteins. Most especially for proteins, Harold Scheraga would play a major role in elucidating the physical principles underlying their molecular behavior. He would go on to provide a molecular understanding of the forces responsible for protein structure and stability, how to predict the native structure of a protein, and how proteins adopt that state, i.e., the mechanism of protein folding. These have been the long-term objectives that Harold has pursued throughout his long and illustrious career. His initial efforts at Cornell concentrated on hydrodynamic experiments to determine the size and shape of proteins. At the time, there were three-competing theories, Kirkwood−Riseman, Debye−Bueche, and Flory−Fox, for explaining the hydrodynamic properties of solutions of synthetic polymers. In collaboration with Nobel Prize winning polymer chemist Paul Flory, based on results from ultracentrifugation and viscosity measurements on polyisobutylene, they concluded that Flory−Fox theory was closest to experiment. With confidence in the Flory−Fox hydrodynamic theory of spherical polymers, Harold and a Flory postdoc, Leo Mandelkern, extended the theory to flexible ellipsoidal models of proteins, and found that many earlier hydrodynamic studies of protein solutions were misinterpreted. For example, fibrinogen from blood plasma was previously alleged to be a rod-like molecule with an axial ratio of 18:1. However, Scheraga−Mandelkern theory showed that it was 5:1. This was in agreement with the value proposed by Cecil Hall on the basis of electron microscopy. At the same time, Harold, with his first graduate student, Michael Laskowski, Jr., investigated the thrombin-induced conversion of fibrinogen to a fibrin clot, a fundamental process in blood clotting, and deduced a reversible kinetic mechanism for fibrin clot formation. These studies also provided molecular insight into a bleeding disorder arising from a mutation in fibrinogen’s amino acid sequence. These studies of fibrinogen were extended in later years to provide more of the molecular details of the blood clotting process. A dramatic series of events occurred in the early 1950s that transformed the view of a protein from a colloidal particle (for which one could determine its size and shape from hydrodynamic measurements) to a real molecular entity: Fred Sanger’s determination of the amino acid sequence of insulin and Linus Pauling’s proposal of the α and β secondary structures, with emphasis on backbone hydrogen bonds. Simultaneously, Crick and Watson proposed the double-helical structure of DNA. This led to a large effort in many laboratories to study α-helix−coil transitions in polypeptides (and polynucleotides) as a model of protein unfolding and folding. In a tour de force, Harold, together with many students, used random copolymers of amino acids in a host−guest technique to determine the helix-forming tendency of all 20 naturally occurring amino acids. With Douglas Poland, Harold analyzed the statistical mechanical basis for phase transitions in