title: Accelerated convergence of molecular free energy via superposition approximation-based reference states.
abstract: The free energy of a molecular system can, at least in principle, be computed by thermodynamic perturbation from a reference system whose free energy is known. The convergence of such a calculation depends critically on the conformational overlap between the reference and the physical systems. One approach to defining a suitable reference system is to construct it from the one-dimensional marginal probability distribution functions (PDFs) of internal coordinates observed in a molecular simulation. However, the conformational overlap of this reference system tends to decline steeply with increasing dimensionality, due to the neglect of correlations among the coordinates. Here, we test a reference system that can account for pairwise correlations among the internal coordinates, as captured by their two-dimensional marginal PDFs derived from a molecular simulation. Incorporating pairwise correlations in the reference system is found to dramatically improve the convergence of the free energy estimates relative to the first-order reference system, due to increased conformational overlap with the physical distribution.
authors.affiliation: Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Somani
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D011336:Probability; D011407:Propane / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D010455:Peptides; D011407:Propane