title: OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins.
abstract: The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Harder
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Damm
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Maple
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Chuanjie
authors.initials: C
authors.lastname: Wu
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Reboul
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Jin Yu
authors.initials: JY
authors.lastname: Xiang
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Lingle
authors.initials: L
authors.lastname: Wang
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lupyan
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Dahlgren
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Knight
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Kaus
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Cerutti
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Goran
authors.initials: G
authors.lastname: Krilov
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.affiliation: Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
authors.affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friesner
mesh_terms: D000465:Algorithms; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D011789:Quantum Theory; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D008024:Ligands; D010455:Peptides; D011506:Proteins; D054852:Small Molecule Libraries; D051357:Cyclin-Dependent Kinase 2