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Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease.

ABSTRACT: Computational analysis of protein-ligand interactions is of crucial importance for drug discovery. Assessment of ligand binding energy allows us to have a glimpse of the potential of a small organic molecule to be a ligand to the binding site of a protein target. Available scoring functions, such as in docking programs, all rely on equations that sum each type of protein-ligand interactions in order to predict the binding affinity. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. Electrostatic interactions constitute one of the most important part of total interactions between macromolecules. Unlike dispersion forces, they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In this study, complexes of HIV-1 protease with inhibitor molecules (JE-2147 and darunavir) were analyzed by using charge densities from the transferable aspherical-atom University at Buffalo Databank (UBDB). Moreover, we analyzed the electrostatic interaction energy for an ensemble of structures, using molecular dynamic simulations to highlight the main features of electrostatic interactions important for binding affinity.

SUBMITTER: Kumar P

PROVIDER: S-EPMC8270314 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Accurate and fast evaluation of electrostatic interactions in molecular systems is one of the most challenging tasks in the rapidly advancing field of macromolecular chemistry and drug design. Electrostatic interactions are of crucial importance in biological systems. They are well represented by quantum mechanical methods; however, such calculations are computationally expensive. In this study, we have evaluated the University of Buffalo Pseudoatom Databank (UBDB)1,2 approach for approximation of electrostatic properties of macromolecules and their complexes. We selected the S663 and JSCH-20054 data sets (208 molecular complexes in total) for this study. These complexes represent a wide range of chemical and biological systems for which hydrogen bonding, electrostatic, and van der Waals interactions play important roles. Reference electrostatic energies were obtained directly from wave functions at the B3LYP/aug-cc-pVTZ level of theory using the SAPT (Symmetry-Adapted Perturbation Theory) scheme for calculation of electrostatic contributions to total intermolecular interaction energies. Electrostatic energies calculated on the basis of the UBDB were compared with corresponding reference results. Results were also compared with energies computed using a point charge model from popular force fields (AM1-BCC and RESP used in AMBER and CGenFF from CHARMM family). The energy trends are quite consistent (R2 ≈ 0.98) for the UBDB method as compared to the AMBER5 and CHARMM force field methods6(R2 ≈ 0.93 on average). The RSMEs do not exceed 3.2 kcal mol-1 for the UBDB and are in the range of 3.7-7.6 kcal mol-1 for the point charge models. We also investigated the discrepancies in electrostatic potentials and magnitudes of dipole moments among the tested methods. This study shows that estimation of electrostatic interaction energies using the UBDB databank is accurate and reasonably fast when compared to other known methods, which opens potential new applications to macromolecules.

Dataset Information

Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease.

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