Non-bonded force field parameters from MBIS partitioning of the molecular electron density improve binding affinity predictions of the T4-lysozyme double mutant

30 November 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Binding affinity prediction using 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. 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 method (MBIS) 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, both when it is bound and unbound. In addition, we have validated a simulation procedure that accounts for the protein and the ligand degrees of freedom to precisely calculate binding free energies. This was achieved by comparing the self-adjusted mixture sampling and non-equilibrium 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 the validated simulation procedure. This improvement surpasses the chemical precision for the eight aromatic ligands reaching a root mean square error (RMSE) of 0.7 kcal/mol.

Keywords

MBIS non-bonded force field parameters
T4 lysozyme
absolute binding free energy

Supplementary materials

Title
Description
Actions
Title
Supporting Information
Description
Polarization energies of all ligands in the bound and unbound states, comparison of Lennard-Jones parameters, workflow for non-bonded force field parameter derivation, RMSD of Helix F for the eight protein-ligand complexes, atomic charges for all ligands.
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.