Life on Earth is supported by water-based processes, including acid-base equilibrium, where pH plays a major role. Solvent pH affects the protonation states of major titratable residues in proteins, which in turn influences many of its molecular properties like structure, function, and catalysis. Computational methods are important in understanding these pH-dependent properties as they are able to validate experimental measures, besides providing additional atomic level information. Our group has implemented and validated pH Replica Exchange Methods (pH REMD) in AMBER. As an application to pH-REMD, we have recently studied the pH-dependent conformational changes in the SNase mutants, L25K and L125K. Our calculations show that the observed pKaof the internal Lys25 and Lys125 are significantly deviated from their intrinsic pKa, in consistence with experiments. Using thermodynamic laws, we estimated the ‘microscopic conformation-specific pKa’ of these internal lysine residues and explain their association with the ‘macroscopic observed pKa’. We have also studied the pH-dependent properties of internal ion-pairs in SNase. Another system under study is the E.coliGlycinamide ribonucleotide transformylase(GAR Tfase), which is a cancer target. E.coliGAR Tfase exhibits pH-dependent structural changes that can alter the binding of ligands and the catalytic activity of the system. We predictedthe pH-activity curve using the population of charged states of key catalytic residues and obtained good agreement with the experimental curve. The knowledge obtained in this study can help inpredictingnew and improved catalytic mechanisms for E.coliGAR Tfase, which can help in the design of efficient inhibitors. Lately, our group has developed methods that allow the theoretical study of electrochemical processes. We have implemented GPU accelerated constant redox potential methods in AMBER. We have also implemented redox potential Replica Exchange MD (E-REMD) and have provided pH and Eas options for multidimensional REMD. We have shown that multidimensional REMD using pH and Edimensions further enhance the convergence of one-dimensional REMD calculations. Among the systems we studied is the Desulfovibrio vulgarisHildenborough cytochrome c3, a relatively small protein that contains four heme groups. Our group is currently working on implementations that allow the theoretical study of Proton-Coupled Electron Transfer (PCET) processes in AMBER.

Exploring pH- and redox-dependent properties of biomolecules

2019 Fall National Meeting

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