Comparative Analysis of Electrostatic Models for Ligand Docking

Author(s)

Sartori, Geraldo Rodrigues ^[1] ; Nascimento, Alessandro S. ^[1]

Affiliation

^[1] Univ Sao Paub, Sao Carlos Inst Phys, Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: FRONTIERS IN MOLECULAR BIOSCIENCES; v. 6, JUL 3 2019.
• Web of Science Citations: 0

Abstract

The precise modeling of molecular interactions remains an important goal among molecular modeling techniques. Some of the challenges in the field include the precise definition of a Hamiltonian for biomolecular systems, together with precise parameters derived from Molecular Mechanics Force Fields, for example. The problem is even more challenging when interaction energies from different species are computed, such as the interaction energy involving a ligand and a protein, given that small differences must be computed from large energies. Here we evaluated the effects of the electrostatic model for ligand binding energy evaluation in the context of ligand docking. For this purpose, a classical Coulomb potential with distance-dependent dielectrics was compared with a Poisson-Boltzmann (PB) model for electrostatic potential computation, based on DelPhi calculations. We found that, although the electrostatic energies were highly correlated for the Coulomb and PB models, the ligand pose and the enrichment of actual ligands against decoy compounds, were improved when binding energies were computed using PB as compared to the Coulomb model. We observed that the electrostatic energies computed with the Coulomb model were, on average, ten times larger than the energies computed with the PB model, suggesting a strong overestimation of the polar interactions in the Coulomb model. We also found that a slightly smoothed Lennard-Jones potential combined with the PB model resulted in a good compromise between ligand sampling and energetic scoring. (AU)

• FAPESP's process: 15/13684-0 - Structural and functional studies of enzymes that participate in complex carbohydrates synthesis and degradation
• Grantee: Igor Polikarpov
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 17/18173-0 - Mechanisms involved in resistance to antibiotics: wall teichoic acids and biofilms as molecular targets
• Grantee: Alessandro Silva Nascimento
• Support type: Regular Research Grants
• FAPESP's process: 15/26722-8 - Drug discovery against human infectious diseases
• Grantee: Carsten Wrenger
• Support type: Research Projects - Thematic Grants