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Harris RC , Deng N , Levy RM , Ishizuka R , Matubayasi N
Computing conformational free energy differences in explicit solvent: An efficient thermodynamic cycle using an auxiliary potential and a free energy functional constructed from the end points
J Comput Chem. 2017 Jun 5;38(15) :1198-1208
PMID: 28008630    PMCID: PMC5403615   
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Many biomolecules undergo conformational changes associated with allostery or ligand binding. Observing these changes in computer simulations is difficult if their timescales are long. These calculations can be accelerated by observing the transition on an auxiliary free energy surface with a simpler Hamiltonian and connecting this free energy surface to the target free energy surface with free energy calculations. Here, we show that the free energy legs of the cycle can be replaced with energy representation (ER) density functional approximations. We compute: (1) The conformational free energy changes for alanine dipeptide transitioning from the right-handed free energy basin to the left-handed basin and (2) the free energy difference between the open and closed conformations of beta-cyclodextrin, a "host" molecule that serves as a model for molecular recognition in host-guest binding. beta-cyclodextrin contains 147 atoms compared to 22 atoms for alanine dipeptide, making beta-cyclodextrin a large molecule for which to compute solvation free energies by free energy perturbation or integration methods and the largest system for which the ER method has been compared to exact free energy methods. The ER method replaced the 28 simulations to compute each coupling free energy with two endpoint simulations, reducing the computational time for the alanine dipeptide calculation by about 70% and for the beta-cyclodextrin by > 95%. The method works even when the distribution of conformations on the auxiliary free energy surface differs substantially from that on the target free energy surface, although some degree of overlap between the two surfaces is required. (c) 2016 Wiley Periodicals, Inc.
1096-987x Harris, Robert C Deng, Nanjie Levy, Ronald M Ishizuka, Ryosuke Matubayasi, Nobuyuki R01 GM030580/GM/NIGMS NIH HHS/United States S10 OD020095/OD/NIH HHS/United States Journal Article United States J Comput Chem. 2017 Jun 5;38(15):1198-1208. doi: 10.1002/jcc.24668. Epub 2016 Dec 23.