Given the importance of free energy calculations in the study of rare events, it is important to develop novel and efficient methods for computing free energy profiles along reaction paths. In this paper, a new approach to the determination of free energy profiles has been introduced. The method is based on the creation of an adiabatic separation between the reaction coordinate and the remaining degrees of freedom within a molecular dynamics simulation. In addition, the reaction coordinate is maintained at a high temperature relative to the remaining degrees of freedom. In this way, the full configuration space corresponding to the rare event is sampled and the free energy profile is rigorously generated directly from the probability distribution of the reaction coordinate. Thus, the new method requires no postprocessing of the data and leads to a scheme that is more efficient than methods based on constraining (or restraining) the reactive degree of freedom.
The new AFED method can be employed in any situation to which other free energy methods can be applied. In particular, in complex biomolecular applications, it offers several advantages in addition to increased efficiency. First, it requires no ``by-hand'' adjustments of the reaction coordinate. Such adjustments, usually needed in the bluemoon ensemble and umbrella sampling methods, can often be difficult to perform for complex reaction coordinates and/or reaction coordinates that are strongly coupled to other degrees of freedom. A good example is that of one or more internal dihedral angle(s). Second, when a definite reaction coordinate is not available, it is expected that the AFED method will allow the free energy profile of a subspace of generalized coordinates to be obtained with greater efficiency than other free energy methods. Testing this hypothesis will be part of future work to be carried out in this area.
Other future will include adapting the method for other types of free energy calculations (e.g. solvation free energies) and combining the AFED method with path integral molecular dynamics [17] for calculation of quantum free energy profiles. The latter will allow, for example, exploration of equilibrium and kinetic isotope effects.