(588e) Improved Configurational Sampling By the the Introduction of Alchemical Variable in Metadynamics

The expanded ensemble technique, an advanced sampling method that utilizes alchemical states to modify the underlying free energy surface, can improve sampling in systems where the physically relevant collective variables are hard to define by intuitions or experimental observations. However, this approach fails if the alchemical variables are almost orthogonal to the most important slow degrees of freedom in the configurational space. Additionally, if there are free energy basins in the alchemical direction or the free energy barriers exist at all lambda states, the system may also get stuck, leading to slow convergence. 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.