Replica exchange metadynamics

Replica exchange methods are typically expensive as they require many (sometimes hundreds) simulations to be run synchronously, often on a large supercomputer facility. Their advantage is that they allow us to accelerate sampling using a minimal amount of a priori knowledge about the specific transition under study. This contrasts with metadynamics, which is very cheap from a computational standpoint but requires physical insight to select proper CVs. 

Thanks to their complementarity, metadynamics and replica exchange can nonetheless be optimally combined.To do so one has to perform simultaneous metadynamics simulations and adjust the Metropolis criterion to include the bias potential... 

Notably, metadynamics can also be combined with replica exchange techniques other than parallel tempering, for example, solute tempering. ... 

Using BEMD it is thus possible to replace an (unfeasible) metadynamics that would use ten or twenty CVs with ten or twenty weakly coupled one-dimensional metadynamics simulations and retain an accuracy that is determined by the replica containing the optimal CV. Moreover, the statistics of each of the replicas benehts from the exchange. Accordingly, the exploration of phase space by each replica is much higher compared to that of a simple MetaD. We hnally point out that in BEMD the statistics produced by all the replicas should be used to calculate the final free-energy landscape via a reweighting procedure. 

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