Free Energy Density of a Fluid and Its Role in Solvation and Binding

• DOI: 10.1021/acs.jctc.3c01173
• Publication Date: 2024-03-27T15:18:31Z
• Authors: Michael K Gilson; Tom Kurtzman
• Keywords: Thermodynamic integration; Position (finance); Energy density; Zero (linguistics)

The concept that a fluid has position-dependent free energy density appears in the literature but not been fully developed or accepted. We set this on an unambiguous theoretical footing via following strategy. First, we forth four desiderata should be satisfied by any definition of density, f(R), system comprising only and rigid solute: its volume integral, plus fixed internal solute, energy; it deviates from bulk value, fbulk, near solute asymptotically approach fbulk with increasing distance solute; go to zero where solvent goes zero; well-defined most general case made up flexible molecules arbitrary interaction potential. Second, use statistical thermodynamics formulate satisfies these desiderata. Third, show how satisfying may used analyze molecular processes solution. In particular, because spatial integral f(R) equals system, can compute changes result rearrangement solutes as well forces exerted solvent. This enables thermodynamic analysis water protein binding sites inform ligand design. Finally, discuss related address published concerns regarding plausibility density. theory presented here applications computational chemistry further generalizable beyond fluids, such solids macromolecules.