Rapid Decomposition and Visualisation of Protein-Ligand Binding Free Energies by Residue and by Water

Woods CJ, Malaisree M, Julien Michel, Long Ben, McIntosh-Smith S, Mulholland AJ

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Recent advances in computational hardware, software and algorithms enable simulations of protein–ligand complexes to achieve timescales during which complete ligand binding and unbinding pathways can be observed. While observation of such events can promote understanding of binding and unbinding pathways, it does not alone provide information about the molecular drivers for protein–ligand association, nor guidance on how a ligand could be optimised to better bind to the protein. We have developed the waterswap (C. J. Woods et al., J. Chem. Phys., 2011, 134, 054114) absolute binding free energy method that calculates binding affinities by exchanging the ligand with an equivalent volume of water. A significant advantage of this method is that the binding free energy is calculated using a single reaction coordinate from a single simulation. This has enabled the development of new visualisations of binding affinities based on free energy decompositions to per-residue and per-water molecule components. These provide a clear picture of which protein–ligand interactions are strong, and which active site water molecules are stabilised or destabilised upon binding. Optimisation of the algorithms underlying the decomposition enables near-real-time visualisation, allowing these calculations to be used either to provide interactive feedback to a ligand designer, or to provide run-time analysis of protein–ligand molecular dynamics simulations.
Original languageEnglish
Pages (from-to)477-499
JournalFaraday Discussions
Early online date31 Jan 2014
Publication statusPublished - 1 Nov 2014


Dive into the research topics of 'Rapid Decomposition and Visualisation of Protein-Ligand Binding Free Energies by Residue and by Water'. Together they form a unique fingerprint.

Cite this