biostudies-literatureYousefi RNational Institute of General Medical SciencesNIGMS NIH HHSCancer Prevention and Research Institute of TexasNational Science Foundation104110https://www.ebi.ac.uk/biostudies/studies/S-EPMC8439718biostudies-literatureUnknown155(10)The proximal distribution function (pDF) quantifies the probability of finding a solvent molecule in the vicinity of solutes. The approach constitutes a hierarchically organized theory for constructing approximate solvation structures around solutes. Given the assumption of universality of atom cluster-specific solvation, reconstruction of the solvent distribution around arbitrary molecules provides a computationally convenient route to solvation thermodynamics. Previously, such solvent reconstructions usually considered the contribution of the nearest-neighbor distribution only. We extend the pDF reconstruction algorithm to terms including next-nearest-neighbor contribution. As a test, small molecules (alanine and butane) are examined. The analysis is then extended to include the protein The Journal of chemical physicsContributions of higher-order proximal distribution functions to solvent structure around proteins.PMC8439718CHE-1709310RP170593GM037657R01 GM037657Yousefi RPettitt BMLynch GCGalbraith MfalseContributions of higher-order proximal distribution functions to solvent structure around proteins.The proximal distribution function (pDF) quantifies the probability of finding a solvent molecule in the vicinity of solutes. The approach constitutes a hierarchically organized theory for constructing approximate solvation structures around solutes. Given the assumption of universality of atom cluster-specific solvation, reconstruction of the solvent distribution around arbitrary molecules provides a computationally convenient route to solvation thermodynamics. Previously, such solvent reconstructions usually considered the contribution of the nearest-neighbor distribution only. We extend the pDF reconstruction algorithm to terms including next-nearest-neighbor contribution. As a test, small molecules (alanine and butane) are examined. The analysis is then extended to include the protein 2021-01-01T00:00:00Z2021 Sep2025-04-26T07:18:16.972Z2025-04-06T12:12:48.349ZS-EPMC84397183452581710.1063/5.0062580