Zooming in on Solvation Free Energy Surfaces in Atomistic Simulations

Abstract

Changes in free energy are generally the sum of multiple contributions that include changes in the internal energy of flexible molecules, their conformational entropy and solvation free energy. Often these individual contributions are large in magnitude and of opposite sign, leading to a significant compensation of favorable and unfavorable terms. To obtain a detailed understanding of thermodynamic driving forces that are responsible for conformational fluctuations of proteins and enzymes, aggregation, self-assembly, and molecular recognition, microscopic insights into the origins of the distinct free energy contributions are required. We present here applications of a novel spatially resolved analysis (3D-2PT) of local solvation enthalpy and entropy contributions, which define the solvation free energy surface of individual biomolecules and solvent-mediated interactions between them. Our analysis is based on atomistic molecular dynamics simulations, which we employ to quantify variations in the solvation free energy of proteins along conformational transitions. Further, we demonstrate how the results of our analysis can be employed to improve the description of solvent-mediated interactions in meso-scale simulations with implicit solvent models. Finally, we correlate local solvent thermodynamics to chemical and topological properties of hydrated biomolecular surfaces and local retardations of dynamical processes in the hydration shell. Such correlations elucidate the relevant microscopic factors that determine favorable and unfavorable solvation free energies and allow for the formulation of computationally efficient predictions.