On the Convergence of Metadynamics with Gaussian Hills

Abstract

Metadynamics is a class of enhanced-sampling methods that is widely used in molecular modeling. Here, we consider metadynamics with a one-dimensional collective variable and explore the limitations of using Gaussian hills in light of existing convergence results. We reduce the corresponding evolution problem to a replicator-type differential equation and analyze its long-time behavior. For a periodic collective variable, we prove the convergence of metadynamics. However, the situation is fundamentally different when the collective variable is defined on a finite interval. In this case, the stationary solution only exists in the weak sense as a finite atomic measure. The solution to the differential equation weakly converges to it. Consequently, metadynamics is ineffective due to the absence of a clear quasi-stationary state. A quasi-stationary, transient solution can only be captured in the "INTERVAL" framework if the free energy outside the finite interval remains nearly constant across sufficiently large regions compared to $σ$.