More than a half century ago it became feasible to simulate, using classical-mechanical
equations of motion, the dynamics of molecular systems on a computer. Since then classical …

Although molecular dynamics simulations have become a useful tool in essentially all fields
of chemistry, condensed matter physics, materials science, and biology, there is still a large …

Alchemical free energy calculations are a useful tool for predicting free energy differences
associated with the transfer of molecules from one environment to another. The hallmark of …

Highlights•Binding free energy calculations are increasing used in drug design and
biotechnology.•We distinguish end-state methods, alchemical methods and pathway …

Free energy calculations are rapidly becoming indispensable in structure-enabled drug
discovery programs. As new methods, force fields, and implementations are developed …

In drug discovery, the in silico prediction of binding affinity is one of the major means to
prioritize compounds for synthesis. Alchemical relative binding free energy (RBFE) …

Relative binding free energy calculations have become an integral computational tool for
lead optimization in structure-based drug design. Classical alchemical methods, including …

Alchemical free-energy methods based on molecular dynamics (MD) simulations have
become important tools to identify modifications of small organic molecules that improve …

Free-energy differences between pairs of end-states can be estimated based on molecular
dynamics (MD) simulations using standard pathway-dependent methods such as …

Alchemical free energy calculations typically rely on intermediate states to bridge between
the relevant phase spaces of the two end states. These intermediate states are usually …