A Transfer Free Energy Based Implicit Solvent Model for Protein Simulations in Solvent Mixtures: Urea-Induced Denaturation as a Case Study

A Arsiccio and P Ganguly and JE Shea, JOURNAL OF PHYSICAL CHEMISTRY B (2022).

DOI: 10.1021/acs.jpcb.2c00889

We developed a method for implicit solvent molecular dynamics simulations of proteins in solvent mixtures (model with implicit solvation thermodynamics, MIST). The MIST method introduces experimental group transfer free energies to the generalized Born formulation for generating molecular trajectories without the need for developing rigorous explicit-solvent force fields for multicomponent solutions. As a test case, we studied the ureainduced denaturation of the Trp-cage miniprotein in water. We demonstrate that our method allows efficient exploration of the conformational space of the protein in only a few hundreds of nanoseconds of all-atom unbiased simulations. Furthermore, selective implementation of the transfer free energies of specific peptide groups, backbone, and side chains enables us to decouple their specific energetic contributions to the conformational changes of the protein. The approach herein developed can readily be extended to the investigation of complex matrices as well as to the characterization of protein aggregation. The MIST method is implemented in Plumed (ver. 2.8) as a separate module called SASA.

Return to Publications page