Optimised Potentials for Liquid Simulations
The industry-standard force fields for organic molecules, proteins, nucleic acids, and lipids. Developed over four decades by the Jorgensen group at Yale, OPLS parameters are fitted to reproduce experimental liquid properties — densities, heats of vaporisation, and free energies of hydration — ensuring accuracy in condensed-phase simulations.
OPLS (Optimised Potentials for Liquid Simulations) is a family of force fields developed by the Jorgensen group with a defining philosophy: parameters must reproduce experimental liquid-state data, not just gas-phase quantum chemistry. Each functional group is parametrised to match measured densities, heats of vaporisation, and free energies of solvation for neat liquids and aqueous solutions. The result is a force field that performs with exceptional accuracy in the condensed phase — where nearly all chemistry of interest actually occurs. OPLS-AA (all-atom) and its successor OPLS-AA/L are the default parameter sets used throughout the foundation's simulation programs.
Organic Small Molecules
Complete OPLS-AA coverage for common organic functional groups: alkanes, alkenes, aromatics, alcohols, ethers, esters, amines, amides, halides, thiols, and heterocycles. Torsional parameters fitted to reproduce both liquid properties and high-level QM conformational profiles.
Proteins and Peptides
All 20 standard amino acids parametrised with OPLS-AA/L backbone dihedral corrections. Improved helical propensity balance relative to OPLS-AA, validated against NMR data for dipeptides and short helices. Covers common post-translational modifications and non-standard residues.
Nucleic Acids
DNA and RNA bases, sugars, and phosphate backbone parametrised for explicit-solvent simulations. Compatible with standard nucleotide residue topologies. Suitable for DNA duplex stability, RNA folding, and protein-nucleic acid interaction studies.
Lipids and Membranes
Phospholipid parameters for bilayer simulations. Compatible with standard glycerophospholipid head groups and common fatty acid tails. Used for membrane protein embedding and lipid-drug interaction studies in conjunction with the TIP3P/TIP4P water models.
Water Models
TIP3P, TIP4P, and TIP5P water models developed alongside and validated with OPLS parameters. TIP4P reproduces the density maximum of water near 4 °C; TIP5P further improves structural properties. All are compatible with OPLS-AA solute parameters for mixed systems.
Ion Parameters
Monovalent and divalent ion parameters fitted to experimental free energies of hydration and ion-water radial distribution functions. Covers alkali metals, halides, and common divalent cations for ionic solution and nucleic acid simulations.
OPLS-UA (United-Atom)
The original OPLS force field introduced in 1984, using united-atom (UA) groups where non-polar hydrogens are merged into the heavy atom they are bonded to. Reduces the number of interaction sites by roughly a third, improving simulation speed. UA parameters were fitted to reproduce densities and heats of vaporisation for a broad range of organic liquids. Still widely used for hydrocarbon and simple organic systems where explicit aliphatic hydrogens are not essential.
OPLS-AA (All-Atom)
All-atom parametrisation published in 1996 that places explicit parameters on every hydrogen. Non-bonded parameters (ε, σ, q) refitted to experimental liquid properties for 14 functional group classes covering over 30 organic liquids. Intramolecular torsional terms fitted to HF/6-31G* energy profiles for representative molecules. OPLS-AA is the base parameter set for all protein and biomolecular simulations in BOSS, MCPRO, and the FEP modules.
OPLS-AA/L (Improved Backbone)
Backbone dihedral corrections published by Kaminski et al. in 2001, addressing the over-stabilisation of helical conformations in OPLS-AA. New φ and ψ torsional terms for alanine and glycine dipeptides fitted to LMP2/cc-pVTZ(-f)//HF/6-31G** energy surfaces. Side-chain parameters unchanged from OPLS-AA. OPLS-AA/L reproduces α-helix:β-sheet equilibria in better agreement with experiment and is the default protein parameter set used in the foundation's programs.
Partial Charge Methodology
Partial charges in OPLS are derived from fitting to HF/6-31G* electrostatic potentials (RESP methodology) and then empirically scaled to reproduce condensed-phase properties. This 1.14× scaling relative to AM1-BCC or restrained ESP charges compensates for the mean-field approximation implicit in fixed-charge force fields and captures average electronic polarisation in the condensed phase without explicit polarisability terms.
Combining Rules and Non-Bonded Interactions
OPLS uses geometric mean combining rules for both ε (well depth) and σ (diameter) Lennard-Jones parameters between unlike atom types: εᵢⱼ = √(εᵢεⱼ), σᵢⱼ = √(σᵢσⱼ). This differs from the Lorentz-Berthelot rules used in AMBER and CHARMM and reflects the liquid-property fitting procedure. 1-4 non-bonded interactions are scaled by 0.5 for both LJ and electrostatic terms. Cutoff distances of 8–12 Å are standard depending on system size.
Validation Benchmarks
OPLS parameters are validated against experimental liquid densities (ρ), heats of vaporisation (ΔHvap), and free energies of hydration (ΔGhyd) for each functional group class. Typical accuracy: ρ within 1–2%, ΔHvap within 1–2 kJ/mol, ΔGhyd within 1 kcal/mol. Additional validation includes NMR coupling constants for backbone conformational equilibria (OPLS-AA/L) and protein folding stability benchmarks against experimentally characterised helical peptides.
What OPLS reads
Molecular structure (.mol2 / .sdf)
Small-molecule structures for automatic parameter assignment. The platform's parameter engine identifies OPLS atom types from connectivity, assigns charges via AM1-BCC scaled to the OPLS convention, and generates a ready-to-use parameter file.
Protein / nucleic acid structure (.pdb)
Standard PDB files for biomolecular systems. Residue-based topology assignment using OPLS-AA/L residue libraries. Handles standard amino acids, common modified residues, and nucleotides.
SMILES string
Direct SMILES input for small molecules. 3D conformation generated automatically, followed by OPLS atom type assignment and charge calculation. Suitable for rapid parameter generation in screening workflows.
Custom parameter override (.par)
User-supplied non-bonded and torsional parameters for novel functional groups, non-standard residues, or bespoke force field modifications. Merged with the standard OPLS library at runtime.
What OPLS returns
Parameter file (.par)
Complete OPLS parameter file for the input molecule, including atom types, partial charges, LJ parameters, and torsional terms. Directly usable in BOSS, MCPRO, and FEP calculations without modification.
Z-matrix file (.z)
Internal coordinate representation of the parametrised molecule with OPLS atom type labels and connectivity. Required input format for Monte Carlo simulations in BOSS and MCPRO.
Predicted liquid properties
For parametrised pure liquids: predicted density and heat of vaporisation from short Monte Carlo simulations, compared against experimental reference values to confirm parameter quality before production runs.
Atom type assignment log
Record of every atom type assignment decision, partial charge values, and any ambiguous cases flagged for user review. Downloadable for documentation and supplementary methods sections.
Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids
Journal of the American Chemical Society · 1996 · Vol. 118, pp. 11225–11236
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.
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