Large-scale molecular dynamics simulation: Effect of polarization on thrombin-ligand binding energy.

Li L Duan,Guo Q Feng,Qing G Zhang

doi:10.1038/srep31488

Abstract

Molecular dynamics (MD) simulations lasting 500 ns were performed in explicit water to investigate the effect of polarization on the binding of ligands to human α-thrombin based on the standard nonpolarizable AMBER force field and the quantum-derived polarized protein-specific charge (PPC). The PPC includes the electronic polarization effect of the thrombin-ligand complex, which is absent in the standard force field. A detailed analysis and comparison of the results of the MD simulation with experimental data provided strong evidence that intra-protein, protein-ligand hydrogen bonds and the root-mean-square deviation of backbone atoms were significantly stabilized through electronic polarization. Specifically, two critical hydrogen bonds between thrombin and the ligand were broken at approximately 190 ns when AMBER force field was used and the number of intra-protein backbone hydrogen bonds was higher under PPC than under AMBER. The thrombin-ligand binding energy was computed using the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method, and the results were consistent with the experimental value obtained using PPC. Because hydrogen bonds were unstable, it was failed to predict the binding affinity under the AMBER force field. Furthermore, the results of the present study revealed that differences in the binding free energy between AMBER and PPC almost comes from the electrostatic interaction. Thus, this study provides evidence that protein polarization is critical to accurately describe protein-ligand binding.

Highlights

Molecular dynamics (MD) simulations lasting 500 ns were performed in explicit water to investigate the effect of polarization on the binding of ligands to human α-thrombin based on the standard nonpolarizable AMBER force field and the quantum-derived polarized protein-specific charge (PPC)
Electrostatic interaction plays an important role in the dynamic stability of the protein-ligand complex[47]
Because PPC is obtained from the first principal quantum solvation calculation of protein, it accurately represents the polarized electrostatic state of the protein and it should provide more accurate electrostatic interaction than the AMBER force field

Summary

Introduction

Molecular dynamics (MD) simulations lasting 500 ns were performed in explicit water to investigate the effect of polarization on the binding of ligands to human α-thrombin based on the standard nonpolarizable AMBER force field and the quantum-derived polarized protein-specific charge (PPC). A detailed analysis and comparison of the results of the MD simulation with experimental data provided strong evidence that intra-protein, protein-ligand hydrogen bonds and the root-mean-square deviation of backbone atoms were significantly stabilized through electronic polarization. The current force fields including AMBER, CHARMM, GROMACS and OPLS have achieved great success in the past two decades[15,16,17,18,19,20], while fundamental limitations affect their applications They are fitted to high-level quantum mechanical calculations or experimental data for individual amino acids in the gas phase or a homogeneous environment[21]. The development of polarizable force fields is lagging, and the need for a reasonably accurate and efficient force field to accurately represent the electronic polarization state of a protein in a given conformation is becoming increasingly critical

Methods

Results

Conclusion