Improved convergence in dual-topology free energy calculations through use of harmonic restraints

When calculating free energy differences between two molecular systems by means of molecular dynamics simulation, accessory potential functions can help eliminate uninteresting configurational entropy contributions, improve convergence, and facilitate reversibility. In this work, we demonstrate that the use of a harmonic potential function to restrain key portions of a molecular system in a free energy perturbation dual-topology molecular dynamics approach dramatically improves convergence and precision of the calculation. Limitations of this technique are illustrated, and its use in conjunction with a fixed bond-length constraint is developed.