Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations

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Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations

Publisher
BioMed Central
Publication Date
Apr 01, 2003
Source
PMC
Keywords
Disciplines
  • Biology
  • Computer Science
  • Design
  • Medicine
License
Unknown

Abstract

1472-6807-3-2.fm ral ss BioMed CentBMC Structural Biology Open AcceResearch article Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations Ekachai Jenwitheesuk1,2 and Ram Samudrala*1 Address: 1Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA and 2Department of Clinical Microbiology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand Email: Ekachai Jenwitheesuk - [email protected]; Ram Samudrala* - [email protected] * Corresponding author Abstract Background: The accurate prediction of enzyme-substrate interaction energies is one of the major challenges in computational biology. This study describes the improvement of protein-ligand binding energy prediction by incorporating protein flexibility through the use of molecular dynamics (MD) simulations. Results: Docking experiments were undertaken using the program AutoDock for twenty-five HIV-1 protease-inhibitor complexes determined by x-ray crystallography. Protein-rigid docking without any dynamics produced a low correlation of 0.38 between the experimental and calculated binding energies. Correlations improved significantly for all time scales of MD simulations of the receptor-ligand complex. The highest correlation coefficient of 0.87 between the experimental and calculated energies was obtained after 0.1 picoseconds of dynamics simulation. Conclusion: Our results indicate that relaxation of protein complexes by MD simulation is useful and necessary to obtain binding energies that are representative of the experimentally determined values. Background The human immunodeficiency virus type 1 aspartic pro- tease (HIV-1 PR) is an important enzyme due to its key role in viral maturation. Inactivation of the enzyme causes the production of immature, noninfectious viral particles. The enzyme therefore is an attractive target in anti-AIDS drug design, and the effect of binding various inhibitor

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