Extremely precise free energy calculations of amino acid side chain analogs: Comparison of common molecular mechanics force fields for proteins Computational techniques see widespread use in pharmaceutical drug discovery, but typically prove unreliable in predicting trends in protein-ligand binding. Alchemical free energy calculations seek to change that by providing rigorous binding free energies from molecular simulations. Given adequate sampling and an accurate enough force field, these techniques yield accurate free energy estimates. Recent innovations in alchemical techniques have sparked a resurgence of interest in these calculations. Still, many obstacles stand in the way of their routine application in a drug discovery context, including the one we focus on here, sampling. Sampling of binding modes poses a particular challenge as binding modes are often separated by large energy barriers, leading to slow transitions. Binding modes are difficult to predict, and in some cases multiple binding modes may contribute to binding. In view of these hurdles, we present a framework for dealing carefully with uncertainty in binding mode or conformation in the context of free energy calculations. With careful sampling, free energy techniques show considerable promise for aiding drug discovery.

The parametrization and testing of the OPLS all-atom force field for organic molecules and peptides are described. Parameters for both torsional and nonbonded energetics have been derived, while the bond stretching and angle bending parameters have been adopted mostly from the AMBER all-atom force field. The torsional parameters were determined by fitting to rotational energy profiles obtained from ab initio molecular orbital calculations at the RHF/6-31G*//RHF/6-31G* level for more than 50 organic molecules and ions. The quality of the fits was high with average errors for conformational energies of less than 0.2 kcal/mol. The force-field results for molecular structures are also demonstrated to closely match the ab initio predictions. The nonbonded parameters were developed in conjunction with Monte Carlo statistical mechanics simulations by computing thermodynamic and structural properties for 34 pure organic liquids including alkanes, alkenes, alcohols, ethers, acetals, thiols, sulfides, disulfides, aldehydes, ketones, and amides. Average errors in comparison with experimental data are 2% for heats of vaporization and densities. The Monte Carlo simulations included sampling all internal and intermolecular degrees of freedom. It is found that such non-polar and monofunctional systems do not show significant condensed-phase effects on internal energies in going from the gas phase to the pure liquids.

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We present results of improving the OPLS-AA force field for peptides by means of refitting the key Fourier torsional coefficients. The fitting technique combines using accurate ab initio data as the target, choosing an efficient fitting subspace of the whole potential-energy surface, and determining weights for each of the fitting points based on magnitudes of the potential-energy gradient. The average energy RMS deviation from the LMP2/cc-pVTZ(-f)//HF/6-31G** data is reduced by ca. 40% from 0.81 to 0.47 kcal/mol as a result of the fitting for the electrostatically uncharged dipeptides. Transferability of the parameters is demonstrated by using the same alanine dipeptide-fitted backbone torsional parameters for all of the other dipeptides (with the appropriate side-chain refitting) and the alanine tetrapeptide. Parameters of nonbonded interactions have also been refitted for the sulfur-containing dipeptides (cysteine and methionine), and the validity of the new Coulombic charges and the van der Waals σ's and 's is proved through reproducing gas-phase energies of complex formation heats of vaporization and densities of pure model liquids. Moreover, a novel approach to fitting torsional parameters for electrostatically charged molecular systems has been presented and successfully tested on five dipeptides with charged side chains.

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.