Abstract
Evaluating solvation entropies directly and combining with direct energy calculations is one way of calculating free energies of solvation and is used by Inhomogeneous Fluid Solvation Theory (IFST). The configurational entropy of a fluid is a function of the interatomic correlations and can thus be expressed in terms of correlation functions. The entropies in this work are directly calculated from a truncated series of integrals over these correlation functions. Many studies truncate all terms higher than the solvent-solute correlations. This study includes an additional solvent-solvent correlation term and assesses the associated free energy when IFST is applied to a fixed Lennard-Jones particle solvated in neon. The strength of the central potential is varied to imitate larger solutes. Average free energy estimates with both levels of IFST are able to reproduce the estimate made using the Free energy Perturbation (FEP) to within 0.16 kcal/mol. We find that the signal from the solvent-solvent correlations is very weak. Our conclusion is that for monatomic fluids simulated by pairwise classical potentials the correction term is relatively small in magnitude. This study shows it is possible to reproduce the free energy from a path based method like FEP, by only considering the endpoints of the path. This method can be directly applied to more complex solutes which break the spherical symmetry of this study.
Highlights
The ability to estimate the free energy difference between two defined states is a useful tool in computational chemistry
Direct applications are predicting the free energy of a solvation process, whether it may be testing a small molecule in a solvent to see if the pair is likely to be miscible1 or a larger system, for example, a peptide, protein,2 or protein-ligand complex
For the protein-ligand complex, if the free energy of the bound state is less than the unbound state the equilibrium will favour the bound state
Summary
The ability to estimate the free energy difference between two defined states is a useful tool in computational chemistry. Direct applications are predicting the free energy of a solvation process, whether it may be testing a small molecule in a solvent to see if the pair is likely to be miscible or a larger system, for example, a peptide, protein, or protein-ligand complex.3 The latter has a direct implication to in silico drug designs. This work is different from the majority of previous works, in that we truncate the MIE at a higher order, including an additional term This additional term represents correlations between two solvent molecules in the presence of a solute, and such terms have been measured before in the context of water in protein binding pockets using Grid Inhomogeneous Solvation Theory (GIST)..
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