Taming Rugged Free Energy Landscapes Using an Average Force

ConspectusThe observation of complex structural transitions in biological and abiological molecular objects within time scales amenable to molecular dynamics (MD) simulations is often hampered by significant free energy barriers associated with entangled movements. Importance-sampling algorithms, a powerful class of numerical schemes for the investigation of rare events, have been widely used to extend simulations beyond the time scale common to MD. However, probing processes spanning milliseconds through microsecond molecular simulations still constitutes in practice a daunting challenge because of the difficulty of taming the ruggedness of multidimensional free energy surfaces by means of naive transition coordinates. To address this limitation, in recent years we have elaborated importance-sampling methods relying on an adaptive biasing force (ABF). In this Account, we review recent developments of algorithms aimed at mapping rugged free energy landscapes that correspond to complex processes of physical, chemical, and biological relevance. Through these developments, we have broadened the spectrum of applications of the popular ABF algorithm while improving its computational efficiency, notably for multidimensional free energy calculations. One major algorithmic advance, coined meta-eABF, merges the key features of metadynamics and an extended Lagrangian variant of ABF (eABF) by simultaneously shaving the barriers and flooding the valleys of the free energy landscape, and it possesses a convergence rate up to 5-fold greater than those of other importance-sampling algorithms. Through faster convergence and enhanced ergodic properties, meta-eABF represents a significant step forward in the simulation of millisecond-time-scale events. Here we introduce extensions of the algorithm, notably its well-tempered and replica-exchange variants, which further boost the sampling efficiency while gaining in numerical stability, thus allowing quantum-mechanical/molecular-mechanical free energy calculations to be performed at a lower cost. As a paradigm to bridge microsecond simulations to millisecond events by means of free energy calculations, we have applied the ABF family of algorithms to decompose complex movements in molecular objects of biological and abiological nature. We show here how water lubricates the shuttling of an amide-based rotaxane by altering the mechanism that underlies the concerted translation and isomerization of the macrocycle. Introducing novel collective variables in a computational workflow for the rigorous determination of standard binding free energies, we predict with utmost accuracy the thermodynamics of protein–ligand reversible association. Because of their simplicity, versatility, and robust mathematical foundations, the algorithms of the ABF family represent an appealing option for the theoretical investigation of a broad range of problems relevant to physics, chemistry, and biology.