We first present alchemical metadynamics, which allows explicitly biasing configurational collective variables simultaneously with alchemical free energy calculations, entirely within the metadynamics framework. Using test systems with varying complexity, we demonstrate that alchemical metadynamics can enable sampling of configurational metastable states not necessarily accessible in standard free energy methods.
We also introduce the method of replica exchange of expanded ensemble (REXEE), where one which periodically exchanges coordinates of different replicas of expanded ensemble simulations that collectively span the range of interest in the auxiliary variable(s). We show that this method yields free energies consistent with the estimates obtained in expanded ensemble and Hamiltonian replica exchange, but offers significant additional flexibility in how one allocates alchemical states between processors and lessens the need for tight coupling between these processors. It also removes some of the issues that occur with expanded ensemble where state ranges can remain unsampled.
Finally, we present generalizations of REXEE to allow exchange between multiple chemistries, Multiple Topology Replica Exchange (MT-REXEE), and discuss its applications to problems such as enhanced conformational sampling of long alkyl chains via chain growth, the simultaneous sampling of multiple R-group transformations in drug lead optimization, and as a way to easily peform continuous fractional Monte Carlo within molecular dynamics code without modification of the MD code itself.