PREDICTIONS OF FREE-ENERGY DIFFERENCES FROM A SINGLE SIMULATION OF THE INITIAL-STATE

We have investigated the feasibility of using higher derivatives of th e free energy, with respect to a coupling parameter lambda, for predic ting free energy changes between different states from a single simula tion corresponding to the initial state, i.e., lambda=0 in the normal thermodynamic integration approach. Terms up to and including the fift h derivative have been used. For a diatomic with point charges (dipole moment=2.4 D) in a box of water, the free energy corresponding to cha rge rearrangements of the order of +/-0.25e could be predicted accurat ely after 750 ps of simulation and inclusion of the third derivative. Predictions were best for small perturbations. After 1000 ps of simula tion, the first, second, third, and probably the fourth derivatives ha d converged, while the fifth was still oscillating. The possibility of predicting a multitude of free energy changes from a single simulatio n is discussed.