My 65 years in protein chemistry

Abstract

This is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein–protein interactions and to nucleic acids and to protein–nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena.

Dynamical and orientational structural crossovers in low-temperature glycerol

“…About anything related to the protein structure and function has to be described as metastable. Protein itself is unstable to either hydrolysis or association, both bringing it to a thermodynamically more stable state [60]. The function of proteins as enzymes catalyzing specific biochemical reactions is even more affected by the notion of a finite "observation window" [20].…”

Alkanethiolate‐modified Gold Electrode Surfaces Used in Electrochemical Thrombin Detection with Ferrocene‐labeled Fibrinogen

“…Thrombin is an essential protease involved in the coagulation cascade, major thrombotic processes, and hemostasis. Thrombin facilitates blood clotting by converting fibrinogen into fibrin and is regarded as a tumor marker in the diagnosis of pulmonary metastasis . Abnormal concentrations of thrombin in blood have been associated with diseases.…”

“…[1][2][3][4][5] Abnormal concentrations of thrombin in blood have been associated with diseases. Thrombin facilitates blood clotting by converting fibrinogen into fibrin and is regarded as a tumor marker in the diagnosis of pulmonary metastasis.…”

Rosetta and the Journey to Predict Proteins’ Structures, 20 Years on

“…However, before focusing on Rosetta, we present a short overview of fragment assembly PSP methodologies, including Rosetta, and the preliminary studies during the 1995-99 period that contributed to its birth. For the reader with an interest in the overall PSP and protein folding problems, excellent and recent reviews are available in the literature [16][17][18][19][20][21][22][23][24][25] 2. Overview of fragment-based PSP and Rosetta methodology Motivated by the fact there is a strong correlation between sequence and structure at the local level, fragment-based protein structure prediction methods were first proposed in 1994 by Bowie and Eisenberg [26].…”