title: Independent-Trajectory Thermodynamic Integration: a practical guide to protein-drug binding free energy calculations using distributed computing.
abstract: The Independent-Trajectory Thermodynamic Integration (IT-TI) approach for free energy calculation with distributed computing is described. IT-TI utilizes diverse conformational sampling obtained from multiple, independent simulations to obtain more reliable free energy estimates compared to single TI predictions. The latter may significantly under- or over-estimate the binding free energy due to finite sampling. We exemplify the advantages of the IT-TI approach using two distinct cases of protein-ligand binding. In both cases, IT-TI yields distributions of absolute binding free energy estimates that are remarkably centered on the target experimental values. Alternative protocols for the practical and general application of IT-TI calculations are investigated. We highlight a protocol that maximizes predictive power and computational efficiency.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA, USA. mlawrenz@ucsd.edu
authors.forename: Morgan
authors.initials: M
authors.lastname: Lawrenz
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D019295:Computational Biology / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D053139:Oseltamivir / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry; D012984:Software; D013816:Thermodynamics
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins; D011956:Receptors, Cell Surface; D053139:Oseltamivir