Comparative Analysis of Electrostatic Models for Ligand Docking.

Geraldo Rodrigues Sartori,Alessandro S Nascimento

doi:10.3389/fmolb.2019.00052

Geraldo Rodrigues Sartori, Alessandro S Nascimento

Open Access

https://doi.org/10.3389/fmolb.2019.00052

Copy DOI

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.

Highlights

The quantitative description of molecular interactions, at an atomic level, remains an important challenge even in current days of Petascale computing
The calculations of the electrostatic potentials with DelPhi are very fast, typically taking
What is the actual role of PB-based calculation on protein-ligand interactions in the context of ligand docking? In order to address this question, we set up a comparative analysis of ligand binding poses and ligand enrichments using the Coulomb electrostatic model or PB as the electrostatic model to assess the effect of the model in sampling and enrichment, respectively

Summary

Introduction

The quantitative description of molecular interactions, at an atomic level, remains an important challenge even in current days of Petascale computing. Some of the difficulties found in this field include: (i) the energetic description of biomolecular systems; (ii) the fact that binding energies are small differences taken from large energies, resulting in large uncertainties; and (iii) the limited sampling for some calculations Taken together, these obstacles are exactly the challenge of scoring solutions in the docking problem (Halperin et al, 2002). In the context of single point calculations, such as in ligand docking, this challenge remains as an important issue and is handled in some applications with a posterior analysis of ligand candidates using molecular dynamics (MD) or Monte Carlo (MC) simulations to generate an ensemble of thermally accessible configurations of the system and binding energy calculations. The MM-GBSA or MM-PBSA approaches became very popular (Graves et al, 2008; Zhang et al, 2014; Genheden and Ryde, 2015)

Methods

Results

Conclusion