title: Locating binding poses in protein-ligand systems using reconnaissance metadynamics.
abstract: A molecular dynamics-based protocol is proposed for finding and scoring protein-ligand binding poses. This protocol uses the recently developed reconnaissance metadynamics method, which employs a self-learning algorithm to construct a bias that pushes the system away from the kinetic traps where it would otherwise remain. The exploration of phase space with this algorithm is shown to be roughly six to eight times faster than unbiased molecular dynamics and is only limited by the time taken to diffuse about the surface of the protein. We apply this method to the well-studied trypsin-benzamidine system and show that we are able to refind all the poses obtained from a reference EADock blind docking calculation. These poses can be scored based on the length of time the system remains trapped in the pose. Alternatively, one can perform dimensionality reduction on the output trajectory and obtain a map of phase space that can be used in more expensive free-energy calculations.
authors.affiliation: Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule Zurich, and Facoltà di Informatica, Istituto di Scienze Computazionali, Universitá della Svizzera Italiana, Via Giuseppe Buffi 13, 6900 Lugano, Switzerland. par.soderhjelm@phys.chem.ethz.ch
authors.forename: Pär
authors.initials: P
authors.lastname: Söderhjelm
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Tribello
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D000465:Algorithms; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*
chemical_list: D008024:Ligands; D011506:Proteins