Alchemical transformation is a popular route adopted in free energy calculations associated with various biophysical processes, such as protein-ligand binding, or the transfer of a molecule from one environment to another. While the sampling of alchemical intermediate states in either parallel (e.g. Hamiltonian replica exchange) or serial manner (e.g. expanded ensemble) can bridge the gap in the configurational space between two end states of interest, relevant methods could fail in the scenarios where the most important slow degrees of freedom in the configurational space are almost orthogonal to the alchemical variable or the system gets trapped in a deep basin in the alchemical space. <br/><br/>To alleviate these issues, we propose to add alchemical variables as an allowed collective variable in metadynamics, augmenting the ability to sample collective variables. In this study, we validate our implementation of alchemical metadynamics in PLUMED with test systems/alchemical processes with varying complexities and dimensions of collective variable space, including the binding and unbinding of CB8-G3 host-guest binding complex. We show that one-dimensional alchemical metadynamics correctly recovers the free energy difference between the coupled state and the uncoupled state, and show how it can overcome free energy barriers orthogonal to alchemical directions. Multi-dimensional alchemical metadynamics has the potential to further facilitate the sampling by introducing configurational collective variables, now including alchemical parameters, to circumvent barriers in new ways. The method can trivially be combined with other metadynamics-based algorithms implemented in PLUMED. The necessary PLUMED code changes have already been released for general use in PLUMED 2.8.

Accelerated free energy calculations and enhanced configurational sampling by the introduction of alchemical variables in metadynamics

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