Molecular dynamics simulations of ligand recognition upon binding antithrombin: A MM/GBSA approach

Xiaohua Zhang, Horacio Péréz-Sánchez, Felice C Lightstone

Research output: Chapter in Book/Report/Conference proceedingConference contribution

4 Scopus citations

Abstract

A high-throughput virtual screening pipeline has been extended from single energetically minimized structure Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring to ensemble-average MM/GBSA rescoring. For validation, the binding affinities of a series of antithrombin ligands have been calculated by using the two MM/GBSA rescoring methods. The correlation coefficient (R2) of calculated and experimental binding free energies has been improved from 0.36 (for single-structure MM/GBSA rescoring) to 0.69 (for ensemble- average one). Decomposition of the calculated binding free energy reveals the electrostatic interactions in both solute and solvent play an important role in determining the binding free energy. The increasing negative charge of the compounds provides a more favorable electrostatic energy change but creates a higher penalty for the solvation free energy. Such a penalty is compensated by the electrostatic energy change, which results in a better binding affinity. The best binder has the highest ligand efficiency.

Original languageEnglish (US)
Title of host publicationLecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
PublisherSpringer Verlag
Pages584-593
Number of pages10
Volume9044
ISBN (Print)9783319164793
StatePublished - 2015
Externally publishedYes
Event3rd International Work-Conference on Bioinformatics and Biomedical Engineering, IWBBIO 2015 - Granada, Spain
Duration: Apr 15 2015Apr 17 2015

Publication series

NameLecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
Volume9044
ISSN (Print)03029743
ISSN (Electronic)16113349

Other

Other3rd International Work-Conference on Bioinformatics and Biomedical Engineering, IWBBIO 2015
CountrySpain
CityGranada
Period4/15/154/17/15

Keywords

  • Antithrombin
  • Binding affinity
  • Heparin
  • MM/GBSA
  • Molecular dynamics

ASJC Scopus subject areas

  • Computer Science(all)
  • Theoretical Computer Science

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  • Cite this

    Zhang, X., Péréz-Sánchez, H., & Lightstone, F. C. (2015). Molecular dynamics simulations of ligand recognition upon binding antithrombin: A MM/GBSA approach. In Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) (Vol. 9044, pp. 584-593). (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics); Vol. 9044). Springer Verlag.