Pressure-Induced Denaturation of Proteins Studied by Generalized-Ensemble Molecular Simulations

Abstract

The pressure dependence of several proteins has recently been studied both experimentally and theoretically. Some of the experiments showed that proteins are denatured under high pressure conditions. We would like to understand the molecular mechanism of the pressure-induced denaturation of proteins by using molecular dynamics simulations.Molecular dynamics simulations have been widely used for studying biomolecular systems. However, the molecular simulations of biomolecular systems often get trapped in local minimum energy states. One way to overcome such a difficulty is to use generalized-ensemble algorithms. Using generalized-ensemble algorithms in molecular simulations, we can sample protein conformations efficiently and calculate physical quantities accurately. We have recently developed a generalized-ensemble algorithm for the isobaric-isothermal ensemble. This method can be used to calculate accurate temperature and pressure dependence of biomolecular systems.In this study we performed molecular simulations of ubiquitin, which is denatured under high pressure conditions. We performed generalized-ensemble molecular dynamics simulations by the NAMD program package. In these simulations, we used one temperature value, 300 K, and one hundred pressure values in range from 1 bar to 10,000 bar.We calculated the fluctuations of the distance between all pairs of amino acid residues. A large distance fluctuation of an amino acid pair means that increasing and decreasing pressure makes the amino acid residues move largely and therefore it is possible that local protein structure changes are induced with increasing and decreasing pressure. The amino acid residues which were largely displaced under high pressure conditions in the experiments correspond to the largely fluctuated amino acid residues in the molecular simulations.