Calculation of Protein Heat Capacity from Replica-Exchange Molecular Dynamics Simulations with Different Implicit Solvent Models

摘要

The heat capacity has played a major role in relating microscopic and macroscopic properties of proteins and their disorder-order phase transition of folding. Its calculation by atomistic simulation methods remains a challenge due to the nature of protein structures, their solvent environment, and configurational averaging. To better understand these factors, we provide a comparative analysis of simulation models that differ in their implicit solvent description and forcefield resolution. Our model protein system is the src Homology 3 (SH3) domain of a-spectrin, and we report a series of 10 ns replica- exchange molecular dynamics simulations performed at temperatures ranging from 298 to 550 K, starting from the SH3 native structure. We apply the all-atom CHARMM22 force field with different modified analytical generalized Born solvent models (GBSW and GBMV2) and compare these simulation models with the distance-dependent dielectric screening of charge-charge interactions. A further comparison is provided with the united-atom CHARMM19 plus a pairwise GB model. Unfolding-folding transition temperatures of SH3 were estimated from temperature-dependent profiles of the heat capacity, root-mean-square distance from the native structure, and the fraction of native contacts, each calculated from the density of states by using the weighted histogram analysis method. We observed that, for CHARMM22, the unfolding transition and energy probability density were quite sensitive to the implicit solvent description, in particular, the treatment of the protein-solvent dielectric boundary in GB models and their surface-areabased hydrophobic term. Among the solvent models tested, the calculated melting temperature varied in the range 353-438 K and was higher than the experimental value near 340 K. A reformulated GBMV2 model of employing a smoother molecular-volume dielectric interface was the most accurate in reproducing the native conformation and a two-state folding landscape, althoug.