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Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine : Insight from Multiple Molecular Dynamics Simulations

Moonsamy, Suri; Bhakat, Soumendranath LU ; Walker, Ross C. and Soliman, Mahmoud E S (2016) In Cell Biochemistry and Biophysics 74(1). p.35-48
Abstract

Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3)... (More)

Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3) variation in the overall enzyme motion as evident from the PCA for both systems, and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Binding free energy calculations, HIV-RT, Lamivudine resistance, M184I mutation, Multiple molecular dynamic simulations
in
Cell Biochemistry and Biophysics
volume
74
issue
1
pages
14 pages
publisher
Humana Press
external identifiers
  • scopus:84961185530
  • wos:000372472400006
ISSN
1085-9195
DOI
10.1007/s12013-015-0709-2
language
English
LU publication?
yes
id
cbc8e095-7206-44d9-aae8-e8aedcd44a11
date added to LUP
2017-02-10 16:11:21
date last changed
2017-09-18 11:38:03
@article{cbc8e095-7206-44d9-aae8-e8aedcd44a11,
  abstract     = {<p>Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3) variation in the overall enzyme motion as evident from the PCA for both systems, and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.</p>},
  author       = {Moonsamy, Suri and Bhakat, Soumendranath and Walker, Ross C. and Soliman, Mahmoud E S},
  issn         = {1085-9195},
  keyword      = {Binding free energy calculations,HIV-RT,Lamivudine resistance,M184I mutation,Multiple molecular dynamic simulations},
  language     = {eng},
  month        = {03},
  number       = {1},
  pages        = {35--48},
  publisher    = {Humana Press},
  series       = {Cell Biochemistry and Biophysics},
  title        = {Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine : Insight from Multiple Molecular Dynamics Simulations},
  url          = {http://dx.doi.org/10.1007/s12013-015-0709-2},
  volume       = {74},
  year         = {2016},
}