λ-dynamics: A new approach to free energy calculations

We present a novel and efficient method for performing free energy calculations. Treating the conventional λ variables associated with the ‘‘progress’’ in the chemical coordinates dynamically, our approach transforms free energy calculations into calculating potentials of mean force in the λ-space with molecular dynamics. This extended Hamiltonian formalism utilizes the full power of umbrella sampling techniques and the weighted histogram analysis method. Applications to free energies of hydration and a model illustrating competitive binding calculations are presented. These calculations demonstrate the robustness and flexibility of the new λ-dynamics approach.