Theoretical and Computational Studies of Pressure Induced Denaturation of Proteins

Rensselaer Polytechnic Institute, Troy NY

Investigators

Abstract

The main objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Biological Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate, is to establish relationship between the thermodynamics and the structural properties of pressure induced changes in proteins using molecular simulations. Pressure provides a way of shifting equilibrium of protein configurations without increasing thermal fluctuations or changing the system composition. Hydrostatic pressure provides a way of probing the role of hydration in protein stability and dynamics. In spite of the wealth of experimental information available, theoretical and computational studies of pressure denaturation have been limited by system size and the slow relaxation of proteins at high pressures. With the development of enhanced sampling techniques, the use of large distributed computing resources, and the development of coarse-grained models for protein folding, these limitations can be overcome. This project will study the effect of high pressure on the stability of peptides that are known to form alpha and beta hairpin structures to determine the effect that high pressure has on the secondary structure stability. To study the effect of tertiary interactions in protein stability, the PI will study the effect of pressure on the stability of mini proteins (Trp-cage) and a small protein (protein A), two systems with simple folds that involve the packing of secondary structure elements. A major challenge will be to study the effect of pressure on larger proteins, such as ubiquitin and SNase. The studies on large proteins will involve coarse-grained models, combined with umbrella sampling techniques on fully solvated systems. The models will be validated by comparing their results with those obtained in unbiased detailed calculations on smaller systems, and by making predictions that can be tested experimentally. The structure and thermodynamics of the unfolded and transition state ensembles to correlate volume effects measured thermodynamically to the degree of hydration of the various ensembles will be studied in detail. This work will establish a framework for understanding the role of water in protein function and stability, as well as for the interpretation of a number of experimental studies of pressure effects on biological molecules. This project is inherently interdisciplinary and it will be done in collaboration with theoretical, computational and experimental groups. Software, models, and algorithms developed in this project will be made available to the scientific community. Students at all levels will be trained in the modeling of thermodynamics properties of biomolecular systems. The PI will train graduate and undergraduate students from both Physics and Biology departments. To enhance the participation of under represented minorities in science, the PI will host researchers and students from the University of Puerto Rico Mayaguez and Humacao.