Simple estimation of absolute free energies for biomolecules.
One reason that free energy difference calculations are notoriously difficult in molecular systems is due to insufficient conformational overlap, or similarity, between the two states or systems of interest. The degree of overlap is irrelevant, however, if the absolute free energy of each state can be computed. We present a method for calculating the absolute free energy that employs a simple construction of an exactly computable reference system which possesses high overlap with the state of interest. The approach requires only a physical ensemble of conformations generated via simulation and an auxiliary calculation of approximately equal central-processing-unit cost. Moreover, the calculations can converge to the correct free energy value even when the physical ensemble is incomplete or improperly distributed. As a "proof of principle," we use the approach to correctly predict free energies for test systems where the absolute values can be calculated exactly and also to predict the conformational equilibrium for leucine dipeptide in implicit solvent.
Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. fmy1@pitt.edu
F Marty
FM
Ytreberg
Daniel M
DM
Zuckerman
D000465:Algorithms; D003198:Computer Simulation; D004151:Dipeptides / Q000737:chemistry*; D008968:Molecular Conformation; D011506:Proteins / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics
D004151:Dipeptides; D011506:Proteins; D012997:Solvents; C038361:leucylleucine