(197al) Advancing Alchemical Free Energy Methods: Enhanced Flexibility, Parallelizability and Configurational Sampling

Over the past decade, alchemical free energy methods have been a popular choice for the computation of solvation free energies and binding free energies, given their ability to connect the end states of interest via nonphysical pathways free from unsurmountable free energy barriers. However, traditional methods like expanded ensemble (EXE) or Hamiltonian replica exchange (HREX) may not be efficient in accurate free energy calculations if the slowest degrees of freedom are largely orthogonal to the alchemical variable. In addition, there exist systems where traversing all alchemical intermediate states is challenging, even if alchemical biases (e.g., in EXE) or coordinate exchanges (e.g., in HREX) are applied. This issue is exacerbated when the state space is multidimensional, which can require seamless communications between hundreds of cores that current parallelization schemes do not fully support.

In this study, we present our recent efforts in addressing these two issues separately. First, we propose alchemical metadynamics, which allows explicitly biasing configurational collective variables in alchemical free energy calculations within the metadynamics framework. With test systems with varying complexity, we demonstrate that alchemical metadynamics captures metastable states not necessarily accessible in traditional free energy methods, thus capable of accurate free energy calculations. For the second issue, we introduce the method of synchronous ensemble of expanded ensemble (EEXE), which periodically exchanges coordinates of different replicas of EXE simulations. We show that this method can compute free energies consistent with the estimates obtained in EXE and HREX, while offering much higher flexibility. Importantly, its planned successor, asynchronous EEXE, performs parallelized simulations asynchronously, which allows close communications between large numbers of adopted processors, and adaptive changes to the parameters of ensembles in response to data collected. These recent efforts can be easily integrated together in ways such as asynchronous ensemble of alchemical metadynamics, promising enhanced flexibility, parallelizability and configurational sampling for a wider ranges of systems.