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We introduce an efficient and robust method to compute alchemical free energydifferences, resulting from the application of multiple walker Adaptive BiasingForce (ABF) in conjunction with strongly damped Langevin $\lambda$-dynamics.Unbiased alchemical free energy surfaces are naturally recovered byThermodynamic Integration (TI). No manual optimization of the $\lambda$schedule is required as the sampling of the $\lambda$ variable is continuousand converges towards a uniform distribution. Free diffusion of $\lambda$improves orthogonal relaxation compared to fixed $\lambda$ methods such asstandard TI or Free Energy Perturbation (FEP). Furthermore, the multiple walkerstrategy provides coverage of orthogonal space in a generic way with minimaluser input and negligible computational overhead. Of practical importance, noadiabatic decoupling between the alchemical and Cartesian degrees of freedom isassumed, ensuring unbiased estimates for a wide envelope of numericalparameters. We present two high-performance implementations of the method inproduction molecular dynamics engines, namely NAMD and Tinker-HP, throughcoupling with the Colvars open source library. These interfaces enable thecombination of the rich feature sets of those packages. We demonstrate thecorrectness and efficiency of the approach on several real-world cases: fromsolvation free energies up to ligand-receptor binding (using a recentlyproposed binding restraint scheme) with both fixed-charge and polarizablemodels. We find that, for a chosen accuracy, the computational cost is stronglyreduced compared to state-of-the-art fixed-lambda methods and that resultswithin 1~kcal/mol of experimental value are recovered for the most complexsystem. The implementation is publicly available and readily usable bypractitioners of current alchemical methods.

Lambda-ABF: Simplified, Accurate and Cost-effective Alchemical Free Energy Computations