Advanced sampling methods involving alchemical transformation, such as expanded ensemble and Hamiltonian replica exchange, are useful for free energy calculations for biomolecular systems. However, there are known issues that such methods could fail if the most important slow degrees of freedom in the configurational space are almost orthogonal to the alchemical variable, or the system gets stuck in the alchemical space. To alleviate this issue, 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. In addition, multi-dimensional alchemical metadynamics has the potential to further facilitate the sampling by introducing configurational collective variables to circumvent barriers. The method can trivially be combined with other metadynamics-based algorithms implemented in PLUMED.

Using alchemical variables within the metadynamics framework to improve sampling in free energy calculations

ACS Spring 2022

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