Comparing the influence of explicit and implicit solvation models on site‐specific thermodynamic stability of proteins

Understanding the molecular basis for protein stability requires a thermodynamic analysis of protein folding. Thermodynamic analysis is often performed by sampling many atomistic conformations using molecular simulations that employ either explicit or implicit water models. However, it remains unclear to what extent thermodynamic results from different solvation models are reliable at the molecular level. In this study, we quantify the influence of both solvation models on folding stability at the individual backbone and side chain resolutions. We assess the residue‐specific folding free energy components of a β‐sheet protein and a helical protein using trajectories resulting from TIP3P explicit and generalized Born/surface area implicit solvent simulations of model proteins. We found that the thermodynamic discrepancy due to the implicit solvent mostly originates from charged side chains, followed by the under‐stabilized hydrophobic ones. In contrast, the contributions of backbone residue in both proteins were comparable for explicit and implicit water models. Our study lays out the foundation for detailed thermodynamic assessment of solvation models in the context of protein simulation. This study is a comparative study of the thermodynamic stabilities of TIP3P and GBSA solvent simulations of representative alpha‐ and beta‐sheet proteins. The molecular‐theory calculations of the free energy components are conducted on protein conformations obtained from molecular dynamics simulations. The site‐directed thermodynamic analysis method is then used to decompose the folding stability into contributions from individual backbones and side chains of protein. From a systematic comparison among residues, the key structural origins of thermodynamic discrepancy owing to GBSA solvent are identified.