title: Flexible docking in solution using metadynamics.
abstract: We apply our recently developed metadynamics method to the docking of ligands on flexible receptors in water solution. This method mimics the real dynamics of a ligand exiting or entering an enzyme and in so doing reconstructs the free energy surface. We apply it to four docking cases: beta-trypsin/benzamidine, beta-trypsin/chlorobenzamidine, immunoglobulin McPC-603/phosphocholine, and cyclin-dependent kinase 2/staurosporine. In every case studied, the method is able to predict the docked geometry and the free energy of docking. Its added value with respect to many other available methods is that it reconstructs the complete free energy surface, including all the relevant minima and the barriers between them.
authors.affiliation: Computational Science, Department of Chemistry and Applied Biosciences, ETH Zürich, USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland. fgervasi@phys.chem.ethz.ch
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laio
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D001550:Benzamidines / Q000737:chemistry* / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D051357:Cyclin-Dependent Kinase 2; D007136:Immunoglobulins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D010767:Phosphorylcholine / Q000737:chemistry* / Q000378:metabolism; D019311:Staurosporine / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D014357:Trypsin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001550:Benzamidines; D007136:Immunoglobulins; D008024:Ligands; D010767:Phosphorylcholine; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D014357:Trypsin; D019311:Staurosporine; C032157:benzamidine