Alchemical Free-Energy Calculations by Multiple-Replica λ-Dynamics: The Conveyor Belt Thermodynamic Integration Scheme.

A new method is proposed to calculate alchemical free-energy differences based on molecular dynamics (MD) simulations, called the conveyor belt thermodynamic integration (CBTI) scheme. As in thermodynamic integration (TI), K replicas of the system are simulated at different values of the alchemical coupling parameter λ. The number K is taken to be even, and the replicas are equally spaced on a forward-turn-backward-turn path, akin to a conveyor belt (CB) between the two physical end-states; and as in λ-dynamics (λD), the λ-values associated with the individual systems evolve in time along the simulation. However, they do so in a concerted fashion, determined by the evolution of a single dynamical variable Λ of period 2π controlling the advance of the entire CB. Thus, a change of Λ is always associated with K/2 equispaced replicas moving forward and K/2 equispaced replicas moving backward along λ. As a result, the effective free-energy profile of the replica system along Λ is periodic of period 2 πK, and the magnitude of its variations decreases rapidly upon increasing K, at least as K in the limit of large K. When a sufficient number of replicas is used, these variations become small, which enables a complete and quasi-homogeneous coverage of the λ-range by the replica system, without application of any biasing potential. If desired, a memory-based biasing potential can still be added to further homogenize the sampling, the preoptimization of which is computationally inexpensive. The final free-energy profile along λ is calculated similarly to TI, by binning of the Hamiltonian λ-derivative as a function of λ considering all replicas simultaneously, followed by quadrature integration. The associated quadrature error can be kept very low owing to the continuous and quasi-homogeneous λ-sampling. The CBTI scheme can be viewed as a continuous/deterministic/dynamical analog of the Hamiltonian replica-exchange/permutation (HRE/HRP) schemes or as a correlated multiple-replica analog of the λD or λ-local elevation umbrella sampling (λ-LEUS) schemes. Compared to TI, it shares the advantage of the latter schemes in terms of enhanced orthogonal sampling, i.e. the availability of variable-λ paths to circumvent conformational barriers present at specific λ-values. Compared to HRE/HRP, it permits a deterministic and continuous sampling of the λ-range, is expected to be less sensitive to possible artifacts of the thermo- and barostating schemes, and bypasses the need to carefully preselect a λ-ladder and a swapping-attempt frequency. Compared to λ-LEUS, it eliminates (or drastically reduces) the dead time associated with the preoptimization of a biasing potential. The goal of this article is to provide the mathematical/physical formulation of the proposed CBTI scheme, along with an initial application of the method to the calculation of the hydration free energy of methanol.