Modeling Ligand–Target Binding with Enhanced Sampling Simulations
Federico Comitani, Francesco Luigi Gervasio · Methods and principles in medicinal chemistry · 2018
This chapter summarizes some of the most successful methods specifically applied to ligand-target binding. Tempering methods artificially increase the temperature of the system, relying on the fact that the rate of free energy barrier crossing events is temperature dependent. A straightforward and convenient strategy to improve the conformational sampling is to simulate the system in multiple copies simultaneously. In parallel tempering, a replica-exchange molecular dynamics (REMD) method, starting from a system at standard room or physiological temperature, the subsequent copies are run at increasingly higher temperatures. Endpoint methods rely on the fact that the free energy is a state function, defined as the difference between the energy of two states and is independent of the paths joining them. Metadynamics, a subset of collective variable-based sampling methods, uses the intriguing idea of a biasing potential that adapts on the fly to the local corrugations of the free energy.