Protein-ligand binding free energies from Ab-Initio quantum mechanical calculations.

Abstract

The accurate prediction of protein-ligand binding free energies with tractable computational methods has the potential to revolutionize drug discovery. Modelling the protein-ligand interaction at a quantum mechanical level, instead of relying on empirical classical mechanical methods, is an essential step toward this goal. In this body of research, we explore the QM-PBSA method to calculate quantum mechanical free energies of binding based on full-protein linear-scaling density functional theory calculations. We apply the QM-PBSA method to the T4-lysozyme L99A/M102Q protein and investigate the convergence, precision, and reproducibility of the QM-PBSA method. Additionally, we compare three different exchange-correlation functionals and different empirical dispersion corrections. Building on our findings in the well-characterized T4-lysozyme we calculate quantum mechanical protein-ligand free energies of binding for a set of ligands binding to the pharmaceutically highly relevant bromodomain containing protein 4 (BRD4) after an extensive investigation of the protein system at the classical mechanical level. BRD4 plays a key role in many cancers. The inhibition of BRD4 can suppress the cancer growth of acute myeloid leukemia, diffuse large B cell lymphoma, prostate cancer, and breast cancer. We demonstrate the predictive power of QM-PBSA in BRD4 as compared to its classical mechanical analog MM-PBSA and show, beyond doubt, that full-protein quantum mechanical calculations are both viable and tractable on modern supercomputers and in an academic context.

More information

Identifiers

ORCID for Lennart Gundelach: orcid.org/0000-0002-7888-8818

ORCID for Chris-Kriton Skylaris: orcid.org/0000-0003-0258-3433

ORCID for Graeme Day: orcid.org/0000-0001-8396-2771

Catalogue record

Export record