Effects of the protonation state in the interaction of an HIV-1 reverse transcriptase (RT) amino acid, Lys101, and a non nucleoside RT inhibitor, GW420867X

  • Sérgio E. Galembeck
  • F. Matthias Bickelhaupt
  • Célia Fonseca Guerra
  • Eduardo Galembeck
Original Paper

DOI: 10.1007/s00894-014-2332-3

Cite this article as:
Galembeck, S.E., Bickelhaupt, F.M., Fonseca Guerra, C. et al. J Mol Model (2014) 20: 2332. doi:10.1007/s00894-014-2332-3
Part of the following topical collections:
  1. Topical Collection Brazilian Symposium of Theoretical Chemistry (SBQT2013)

Abstract

Interactions between an inhibitor and amino acids from a binding pocket could help not only to understand the nature of these interactions, but also to support the design of new inhibitors. In this paper, we explore the key interaction between a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI), GW420867X, and HIV-1 RT amino acid Lys101 (K101), by quantum mechanical methods. The neutral, protonated, and zwitterionic complexes of GW420867X–K101 were studied. The interaction energies were determined by SCS-MP2/def2-cc-pVQZ, and the electron density was analyzed by natural bond orbital (NBO), atoms in molecules (AIM) and reduced gradient analysis. A large increase in the interaction was observed with the tautomerization of neutral or neutral protonated species. The monomers interact by two medium-strength hydrogen bonds, one partially covalent and another noncovalent. There are some van der Waals intramolecular interactions that are topologically unstable. The nature of the intermolecular interactions was also analyzed using quantitative molecular orbital (MO) theory in combination with an energy decomposition analysis (EDA) based on dispersion-corrected density functional theory (DFT) at BLYP-D/TZ2P.

Figure

Structure (left) and gradient isosurface (right) (s = 0.05 a.u.) of the partially relaxed complex of non-nucleoside reverse transcriptase (RT) inhibitor GW420867X with neutral HIV-1 RT amino acid Lys101 (1)

Keywords

AIDS HIV-1 NNRTI NBO QTAIM EDA NCI 

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sérgio E. Galembeck
    • 1
  • F. Matthias Bickelhaupt
    • 2
    • 3
  • Célia Fonseca Guerra
    • 2
  • Eduardo Galembeck
    • 4
  1. 1.Departamento de QuímicaFFCLRP-USPRibeirão PretoBrazil
  2. 2.Department of Theoretical Chemistry, Amsterdam Center for Multiscale Modeling (ACMM)VU University AmsterdamAmsterdamThe Netherlands
  3. 3.Institute of Molecules and MaterialsRadboud University NijmegenNijmegenThe Netherlands
  4. 4.Departamento de BioquímicaIB-UNICAMPCampinasBrazil