title: Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water.
abstract: 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.
authors.affiliation: School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK. Christopher.Woods@bristol.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Woods
authors.forename: Maturos
authors.initials: M
authors.lastname: Malaisree
authors.forename: Julien
authors.initials: J
authors.lastname: Michel
authors.forename: Ben
authors.initials: B
authors.lastname: Long
authors.forename: Simon
authors.initials: S
authors.lastname: McIntosh-Smith
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mulholland
mesh_terms: D000465:Algorithms; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics; D013917:Thrombin / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins; D014867:Water; D013917:Thrombin