  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 (CPU) 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.
