In the calculation of free energies of binding for protein-ligand complexes, we distinguish endpoint methods, methods involving alchemical modifications and methods that physically displace the ligand from the protein. Most methodological advances seem to come from a clever combination of multiple existing methods to enhance the sampling or to utilize specific advantages of various approaches. The coupling parameters common in thermodynamic integration and in Hamiltonian replica exchange are for instance combined to yield replica exchange thermodynamic integration. As new methods mostly aim to improve efficiency or to attain more complete sampling, there are good prospects to understand and tackle the sampling problem better and to shift the focus towards the scoring problem in the context of more robust and accurate force fields.
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