(346y) Introduction of Alchemical Variables in Metadynamics to Enhance Configurational Sampling

Over the past decades, various advanced sampling methods have been developed to address the challenge of comprehensive sampling of the configurational space of systems with a rough free energy surface. As adopted by several well-known algorithms, one common idea of accelerating the sampling is to modify the underlying free energy surface. For example, expanded ensemble utilizes the Wang-Landau algorithm to calculate the biasing weight for each alchemical state based on how frequently the state is visited. While this method circumvents the need of defining a set of collective variables, the system may get stuck in the alchemical space. To alleviate this issue, here we propose to add alchemical variables as an allowed collective variable in metadynamics. With this add-on, metadynamics is no longer restricted to only sampling the configurational collective variables, but is able to sample the alchemical direction as well. 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, from disappearing a lactic acid molecule from water, to the binding and unbinding event of CB8-G3 host-guest binding complex. 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.