Driven metadynamics: Reconstructing equilibrium free energies from driven adaptive-bias simulations

Abstract

We present a novel free-energy calculation method that constructively integrates two distinct classes of nonequilibrium sampling techniques, namely, driven (e.g., steered molecular dynamics) and adaptive-bias (e.g., metadynamics) methods. By employing nonequilibrium work relations, we design a biasing protocol with an explicitly time- and history-dependent bias that uses on-the-fly work measurements to gradually flatten the free-energy surface. The asymptotic convergence of the method is discussed, and several relations are derived for free-energy reconstruction and error estimation. Isomerization reaction of an atomistic polyproline peptide model is used to numerically illustrate the superior efficiency and faster convergence of the method compared with its adaptive-bias and driven components in isolation. © 2013 American Chemical Society.