Assessing the performance of the molecular mechanics/Poisson Boltzmann surface area and molecular mechanics/generalized Born surface area methods. II. the accuracy of ranking poses generated from docking

Tingjun Hou, Junmei Wang, Youyong Li, Wei Wang

Research output: Contribution to journalArticle

403 Scopus citations

Abstract

In molecular docking, it is challenging to develop a scoring function that is accurate to conduct high-throughput screenings. Most scoring functions implemented in popular docking software packages were developed with many approximations for computational efficiency, which sacrifices the accuracy of prediction. With advanced technology and powerful computational hardware nowadays, it is feasible to use rigorous scoring functions, such as molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA) in molecular docking studies. Here, we systematically investigated the performance of MM/PBSA and MM/GBSA to identify the correct binding conformations and predict the binding free energies for 98 protein-ligand complexes. Comparison studies showed that MM/GBSA (69.4%) outperformed MM/PBSA (45.5%) and many popular scoring functions to identify the correct binding conformations. Moreover, we found that molecular dynamics simulations are necessary for some systems to identify the correct binding conformations. Based on our results, we proposed the guideline for MM/GBSA to predict the binding conformations. We then tested the performance of MM/GBSA and MM/PBSA to reproduce the binding free energies of the 98 protein-ligand complexes. The best prediction of MM/GBSA model with internal dielectric constant 2.0, produced a Spearman's correlation coefficient of 0.66, which is better than MM/PBSA (0.49) and almost all scoring functions used in molecular docking. In summary, MM/GBSA performs well for both binding pose predictions and binding free-energy estimations and is efficient to re-score the top-hit poses produced by other less-accurate scoring functions.

Original languageEnglish (US)
Pages (from-to)866-877
Number of pages12
JournalJournal of Computational Chemistry
Volume32
Issue number5
DOIs
StatePublished - Apr 15 2011

Keywords

  • MM/GBSA
  • MM/PBSA
  • Poisson Boltzmann
  • binding free energy
  • generalized Born
  • molecular docking

ASJC Scopus subject areas

  • Chemistry(all)
  • Computational Mathematics

Fingerprint Dive into the research topics of 'Assessing the performance of the molecular mechanics/Poisson Boltzmann surface area and molecular mechanics/generalized Born surface area methods. II. the accuracy of ranking poses generated from docking'. Together they form a unique fingerprint.

  • Cite this