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ABSTRACT: The partitioning of the free energy into additive contributions originating from different groups of atoms or force field
terms has the potential to provide relationship between structure and biological activity of molecules. In this article, the
theoretical foundation for the free energy decomposition in the free energy perturbation (FEP) methodology is formulated using
Thiele cumulants, a powerful tool from the arsenal of probability theory and mathematical statistics. We establish that rigorous
decomposition of the free energy into its components is precluded by the presence of mixed potential energy terms in Thiele
cumulants of second and higher orders. However, we also show that the resultant nonadditivity error can be reduced to an arbitrary
value by increasing the number of FEP steps. Consequently, the whole system can be in the limit of small perturbation steps
adequately represented by the sum of its constituent parts.
Theoretical Chemistry Accounts 03/2007; 117(4):535-540. · 2.16 Impact Factor
