Lettieri, Steven; Mamonov, Artem B.; Zuckerman, Daniel M.
Extending Fragment-Based Free Energy Calculations with Library Monte Carlo Simulation: Annealing in Interaction Space
JOURNAL OF COMPUTATIONAL CHEMISTRY, 32:1135-1143, APR 30 2011

Pre-calculated libraries of molecular fragment configurations have previously been used as a basis for both equilibrium sampling (via library-based Monte Carlo) and for obtaining absolute free energies using a polymer-growth formalism. Here, we combine the two approaches to extend the size of systems for which free energies can be calculated. We study a series of all-atom poly-alanine systems in a simple dielectric solvent and find that precise free energies can be obtained rapidly. For instance, for 12 residues, less than an hour of single-processor time is required. The combined approach is formally equivalent to the annealed importance sampling algorithm; instead of annealing by decreasing temperature, however, interactions among fragments are gradually added as the molecule is grown. We discuss implications for future binding affinity calculations in which a ligand is grown into a binding site. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 32: 1135-1143, 2011

DOI:10.1002/jcc.21695

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