Nonbonded Force Field Parameters from MBIS Partitioning of the Molecular Electron Density Improve Binding Affinity Predictions of the T4-Lysozyme Double Mutant.

The use of computer simulation for binding affinity prediction is growing in drug discovery. However, its wider use is constrained by the accuracy of the free energy calculations. The key sources of error are the force fields used to depict molecular interactions and insufficient sampling of the configurational space. To improve the quality of the force field, we developed a Python-based computational workflow. The workflow described here uses the minimal basis iterative stockholder (MBIS) method to determine atomic charges and Lennard-Jones parameters from the polarized molecular density. This is done by performing electronic structure calculations on various configurations of the ligand when it is both bound and unbound. In addition, we validated a simulation procedure that accounts for the protein and ligand degrees of freedom to precisely calculate binding free energies. This was achieved by comparing the self-adjusted mixture sampling and nonequilibrium thermodynamic integration methods using various protein and ligand conformations. The accuracy of predicting binding affinity is improved by using MBIS-derived force field parameters and a validated simulation procedure. This improvement surpasses the chemical precision for the eight aromatic ligands, reaching a root-mean-square error of 0.7 kcal/mol.

Nonbonded Force Field Parameters from Minimal Basis Iterative Stockholder Partitioning of the Molecular Electron Density Improve CB7 Host-Guest Affinity Predictions.

Binding affinity prediction by means of computer simulation has been increasingly incorporated in drug discovery projects. Its wide application, however, is limited by the prediction accuracy of the free energy calculations. The main error sources are force fields used to describe molecular interactions and incomplete sampling of the configurational space. Organic host-guest systems have been used to address force field quality because they share similar interactions found in ligands and receptors, and their rigidity facilitates configurational sampling. Here, we test the binding free energy prediction accuracy for 14 guests with an aromatic or adamantane core and the CB7 host using molecular electron density derived nonbonded force field parameters. We developed a computational workflow written in Python to derive atomic charges and Lennard-Jones parameters with the Minimal Basis Iterative Stockholder method using the polarized electron density of several configurations of each guest in the bound and unbound states. The resulting nonbonded force field parameters improve binding affinity prediction, especially for guests with an adamantane core in which repulsive exchange and dispersion interactions to the host dominate.

Molecular Environment-Specific Atomic Charges Improve Binding Affinity Predictions of SAMPL5 Host-Guest Systems.

Host-guest systems are widely used in benchmarks as model systems to improve computational methods for absolute binding free energy predictions. Recent advances in sampling algorithms for alchemical free energy calculations and the increase in computational power have made their binding affinity prediction primarily dependent on the quality of the force field. Here, we propose a new methodology to derive the atomic charges of host-guest systems based on quantum mechanics/molecular mechanics calculations and minimal basis iterative stockholder (MBIS) partitioning of the polarized electron density. A newly developed interface between the OpenMM and ORCA software packages provides D-MBIS charges that represent the guest's average electrostatic interactions in the hosts or the solvent. The simulation workflow also calculates the average energy required to polarize the guest in the bound and unbound state. Alchemical free energy calculations using the general Amber force field parameters with D-MBIS charges improve the binding affinity prediction of six guests bound to two octa acid hosts compared to the AM1-BCC charge set after correction with the average energetic polarization cost. This correction originates from the difference in potential energy that is required to polarize the guest in the bound and unbound state and contributes significantly to the binding affinity of anionic guests.