Hepatitis C virus NS5B polymerase: QM/MM calculations show the important role of the internal energy in ligand binding.

Journal Article (Journal Article)

The inter- and intramolecular interactions that determine the experimentally observed binding mode of the ligand (2Z)-2-(benzoylamino)-3-[4-(2-bromophenoxy)phenyl]-2-propenoate in complex with hepatitis C virus NS5B polymerase have been studied using QM/MM calculations. DFT-based QM/MM optimizations were performed on a number of ligand conformers in the protein-ligand complex. Using these initial poses, our aim is 2-fold. First, we identify the minimum energy pose. Second, we dissect the energetic contributions to this pose using QM/MM methods. The study reveals the critical importance of internal energy for the proper energy ranking of the docked poses. Using this protocol, we successfully identified three poses that have low RMSD with respect to the crystallographic structure from among the top 20 initially docked poses. We show that the most important energetic component contributing to binding for this particular protein-ligand system is the conformational (i.e., QM internal) energy.

Full Text

Duke Authors

Cited Authors

  • Parks, JM; Kondru, RK; Hu, H; Beratan, DN; Yang, W

Published Date

  • March 2008

Published In

Volume / Issue

  • 112 / 10

Start / End Page

  • 3168 - 3176

PubMed ID

  • 18271573

Electronic International Standard Serial Number (EISSN)

  • 1520-5207

International Standard Serial Number (ISSN)

  • 1520-6106

Digital Object Identifier (DOI)

  • 10.1021/jp076885j


  • eng