Accelerated convergence of molecular free energy via superposition approximation-based reference states |
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Authors: | Somani Sandeep Gilson Michael K |
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Institution: | Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, USA. |
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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. |
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