Applying efficient implicit nongeometric constraints in alchemical free energy simulations

Abstract Several strategies have been developed for satisfying bond lengths, angle, and other geometric constraints in molecular dynamics simulations. Advanced variations of alchemical free energy perturbation simulations, however, also require nongeometric constraints. In our recently developed multisite λ‐dynamics simulation method, the conventional λ parameters that are associated with the progress variables in alchemical transformations are treated as dynamic variables and are constrained such that: 0 ≤ λ i ≤ 1 and ∑   i = 1 Nλ i = 1. Here, we present four functional forms of λ that implicitly satisfy these nongeometric constraints, whose values and forces are facile to compute and that yield stable simulations using a 2 fs integration timestep. Using model systems, we present the sampling characteristics of these functional forms and demonstrate the enhanced sampling profiles and improved convergence rates that are achieved by the functional form: $\lambda _i = {{e^{c\sin \theta _i } } \over {\sum\nolimits_{j = 1}^N {e^{c\sin \theta _j } } }}$ that oscillates between λ i = 0 and λ i = 1 and has relatively steep transitions between these endpoints. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011