Force Field

Improvements in the OPLS3 Force Field


Realistic atomistic simulation of complex molecular systems is contingent upon the availability of an accurate and reliable molecular mechanics force field. The treatment of systems of interest in biology and materials science typically requires models on the order of thousands to millions of atoms, and timescales from nanoseconds to seconds; even at the low end of both of these ranges, purely quantum mechanical dynamics is extremely expensive (and not necessarily more accurate, as quantum chemical methods that are tractable for systems of this size have deficiencies of their own).  Hence, molecular mechanics force field development has been a central goal of computational chemistry for the past four decades.

OPLS (optimized potentials for liquid simulations) first developed by Jorgensen and coworkers,1,2 was one of the first models in which parameters were extensively optimized to reproduce liquid state thermodynamic properties for a variety of small organic molecules.  This effort yielded a core set of nonbonded (van der Waals) parameters, which still remain at the heart of OPLS development.  OPLS33 represents a next generation model that builds upon this OPLS framework with the following key improvements:

Case Study 1: Impact of an Improved Protein Force Field on Protein-Ligand Binding

Experimental versus FEP-predicted binding free energies over 6 BACE ligands distinguished by their R1 substituent.  Left panel shows the binding mode of the methoxy derivative indicating the position of the functional group varied across the series.   Binding affinities as a function of the R1 functional group shown in the middle panel.  At right, representative structures, taken from simulations of OPLS2.1 and OPLS3, of the Ala396 residue and its associated helix, which enclose the S3 pocket of the BACE1 binding site.

Case Study 2: Impact of an Improved Charge Model on Protein-Ligand Binding

Sub-set of FXA series ligands illustrating electron rich receptor environment from the carboxylate of Asp189 and the backbone carbonyl of Gly219 coordinating aryl nitrogen lone pairs of 17i and 17h.  Binding free energies relative to 17d are tabulated in Table.


Table 5. Experimental and predicted relative binding free energies for FXA ligands.a

17d → 17i3.90.52.1
17d → 17h4.91.03.9

aFree energies are in kcal/mol. Specified ligands are illustrated in Figure 8.  Ligand names are taken from Chan et al.71



  1. Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J., Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc., 1996, 118, 11225-11236.
  2. Harder, E. et al., OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. J. Chem. Theory Comput., 2016, 12(1), 281–296.
  3. Storer, J. W.; Giesen, D. J.; Cramer, C. J.; Truhlar, D. G., Class IV charge models: a new semiempirical approach in quantum chemistry. J. Comput. Aided. Mol. Des., 1995, 9(1), 87-110.
  4. Shivakumar, D.; Harder, E.; Damm, W.; Friesner, R. A.; Sherman, W. J., Improving the Prediction of Absolute Solvation Free Energies Using the Next Generation OPLS Force Field. J. Chem. Theory Comput., 2012, 8, 2553–2558.
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