OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space.

We report on the development and validation of the OPLS4 force field. OPLS4 builds upon our previous work with OPLS3e to improve model accuracy on challenging regimes of drug-like chemical space that includes molecular ions and sulfur-containing moieties. A novel parametrization strategy for charged species, which can be extended to other systems, is introduced. OPLS4 leads to improved accuracy on benchmarks that assess small-molecule solvation and protein-ligand binding.

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo.

The prediction of protein-ligand binding affinities using free energy perturbation (FEP) is becoming increasingly routine in structure-based drug discovery. Most FEP packages use molecular dynamics (MD) to sample the configurations of proteins and ligands, as MD is well-suited to capturing coupled motion. However, MD can be prohibitively inefficient at sampling water molecules that are buried within binding sites, which has severely limited the domain of applicability of FEP and its prospective usage in drug discovery. In this paper, we present an advancement of FEP that augments MD with grand canonical Monte Carlo (GCMC), an enhanced sampling method, to overcome the problem of sampling water. We accomplished this without degrading computational performance. On both old and newly assembled data sets of protein-ligand complexes, we show that the use of GCMC in FEP is essential for accurate and robust predictions for ligand perturbations that disrupt buried water.

Accurate Calculation of Relative Binding Free Energies between Ligands with Different Net Charges.

In drug discovery programs, modifications that change the net charge of the ligands are often considered to improve the binding potency and solubility, or to address other ADME/Tox problems. Accurate calculation of the binding free-energy changes associated with charge-changing perturbations remains a great challenge of central importance in computational drug discovery. The finite size effects associated with periodic boundary condition and lattice summation employed in common molecular dynamics simulations introduce artifacts in the electrostatic potential energy calculations, which need to be carefully handled for accurate free-energy calculations between systems with different net charges. The salts in the buffer solution of experimental binding affinity assays also have a strong effect on the binding free energies between charged species, which further complicates the modeling of the charge-changing perturbations. Here, we extend our free-energy perturbation (FEP) algorithm, which has been extensively applied to many drug discovery programs for relative binding free-energy calculations between ligands with the same net charge (charge-conserving perturbation), to enable charge-changing perturbations. We have investigated three different approaches to correct the finite size effects and tested them on 10 protein targets and 31 charge-changing perturbations. We have found that all three methods are able to successfully eliminate the box-size dependence of calculated binding free energies associated with brute force FEP. Moreover, inclusion of salts matching the ionic strength of experimental buffer solution significantly improves the calculated binding free energies. For ligands with multiple possible protonation states, we applied the p Ka correction to account for the ionization equilibrium of the ligands and the results are significantly improved. Finally, the calculated binding free energies from these methods agree with each other, and also agree well with the experimental results. The root-mean-square error between the calculated binding free energies and experimental data is 1.1 kcal/mol, which is on par with the accuracy of charge-conserving perturbations. We anticipate that the outstanding accuracy demonstrated here across a broad range of target classes may have significant implications for drug discovery projects, where charge-changing modifications must be considered.