OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins

被引:2313
作者
Harder, Edward [1 ]
Damm, Wolfgang [1 ]
Maple, Jon [1 ]
Wu, Chuanjie [1 ]
Reboul, Mark [1 ]
Xiang, Jin Yu [1 ]
Wang, Lingle [1 ]
Lupyan, Dmitry [1 ]
Dahlgren, Markus K. [1 ]
Knight, Jennifer L. [1 ]
Kaus, Joseph W. [1 ]
Cerutti, David S. [1 ]
Krilov, Goran [1 ]
Jorgensen, William L. [3 ]
Abel, Robert [1 ]
Friesner, Richard A. [2 ]
机构
[1] Schrodinger Inc, New York, NY 10036 USA
[2] Columbia Univ, Dept Chem, New York, NY 10027 USA
[3] Yale Univ, Dept Chem, New Haven, CT 06520 USA
关键词
STRUCTURE-BASED DESIGN; HYDRATION FREE-ENERGIES; KINASE INHIBITORS; QUANTUM-CHEMISTRY; SIDE-CHAIN; BIOLOGICAL EVALUATION; DYNAMICS SIMULATIONS; TORSIONAL ENERGETICS; FOLDING SIMULATIONS; TYK2; INHIBITORS;
D O I
10.1021/acs.jctc.5b00864
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
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.
引用
收藏
页码:281 / 296
页数:16
相关论文
共 77 条
[1]   More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of Nonbasic Residues in the S1 Pocket of Thrombin [J].
Baum, Bernhard ;
Mohamed, Menshawy ;
Zayed, Mohamed ;
Gerlach, Christof ;
Heine, Andreas ;
Hangauer, David ;
Klebe, Gerhard .
JOURNAL OF MOLECULAR BIOLOGY, 2009, 390 (01) :56-69
[2]   Toward Automated Benchmarking of Atomistic Force Fields: Neat Liquid Densities and Static Dielectric Constants from the ThermoML Data Archive [J].
Beauchamp, Kyle A. ;
Behr, Julie M. ;
Rustenburg, Arien S. ;
Bayly, Christopher I. ;
Kroenlein, Kenneth ;
Chodera, John D. .
JOURNAL OF PHYSICAL CHEMISTRY B, 2015, 119 (40) :12912-12920
[3]   Are Protein Force Fields Getting Better? A Systematic Benchmark on 524 Diverse NMR Measurements [J].
Beauchamp, Kyle A. ;
Lin, Yu-Shan ;
Das, Rhiju ;
Pande, Vijay S. .
JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 2012, 8 (04) :1409-1414
[4]   THE MISSING TERM IN EFFECTIVE PAIR POTENTIALS [J].
BERENDSEN, HJC ;
GRIGERA, JR ;
STRAATSMA, TP .
JOURNAL OF PHYSICAL CHEMISTRY, 1987, 91 (24) :6269-6271
[5]   Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone φ, ψ and Side-Chain χ1 and χ2 Dihedral Angles [J].
Best, Robert B. ;
Zhu, Xiao ;
Shim, Jihyun ;
Lopes, Pedro E. M. ;
Mittal, Jeetain ;
Feig, Michael ;
MacKerell, Alexander D., Jr. .
JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 2012, 8 (09) :3257-3273
[6]   Jaguar: A high-performance quantum chemistry software program with strengths in life and materials sciences [J].
Bochevarov, Art D. ;
Harder, Edward ;
Hughes, Thomas F. ;
Greenwood, Jeremy R. ;
Braden, Dale A. ;
Philipp, Dean M. ;
Rinaldo, David ;
Halls, Mathew D. ;
Zhang, Jing ;
Friesner, Richard A. .
INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, 2013, 113 (18) :2110-2142
[7]   Healthy skepticism: assessing realistic model performance [J].
Brown, Scott P. ;
Muchmore, Steven W. ;
Hajduk, Philip J. .
DRUG DISCOVERY TODAY, 2009, 14 (7-8) :420-427
[8]   Derivation of Fixed Partial Charges for Amino Acids Accommodating a Specific Water Model and Implicit Polarization [J].
Cerutti, David S. ;
Rice, Julia E. ;
Swope, William C. ;
Case, David A. .
JOURNAL OF PHYSICAL CHEMISTRY B, 2013, 117 (08) :2328-2338
[9]   Factor Xa inhibitors:: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides [J].
Chan, Chuen ;
Borthwick, Alan D. ;
Brown, David ;
Burns-Kurtis, Cynthia L. ;
Campbell, Matthew ;
Chaudry, Laiq ;
Chung, Chun-wa ;
Convery, Maire A. ;
Hamblin, J. Nicole ;
Johnstone, Lisa ;
Kelly, Henry A. ;
Kleanthous, Savvas ;
Patikis, Angela ;
Patel, Champa ;
Pateman, Anthony J. ;
Senger, Stefan ;
Shah, Gita P. ;
Toomey, John R. ;
Watson, Nigel S. ;
Weston, Helen E. ;
Whitworth, Caroline ;
Young, Robert J. ;
Zhou, Ping .
JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (07) :1546-1557
[10]   A 2ND GENERATION FORCE-FIELD FOR THE SIMULATION OF PROTEINS, NUCLEIC-ACIDS, AND ORGANIC-MOLECULES [J].
CORNELL, WD ;
CIEPLAK, P ;
BAYLY, CI ;
GOULD, IR ;
MERZ, KM ;
FERGUSON, DM ;
SPELLMEYER, DC ;
FOX, T ;
CALDWELL, JW ;
KOLLMAN, PA .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1995, 117 (19) :5179-5197