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Effect of T68A/N126Y mutations on the conformational and ligand binding landscape of Coxsackievirus B3 3C protease.

Bhakat, Soumendranath LU (2015) In Molecular BioSystems 11(8). p.2303-2311
Abstract
3C protease of Coxsackievirus B3 (CVB3) plays an essential role in the viral replication cycle, and therefore, emerged as an attractive therapeutic target for the treatment of human diseases caused by CVB3 infection. In this study, we report the first account of the molecular impact of the T68A/N126Y double mutant (MutantBound) using an integrated computational approach. Molecular dynamics simulation and post-dynamics binding free energy, principal component analysis (PCA), hydrogen bond occupancy, SASA, Rg and RMSF confirm that T68A/N126Y instigated an increased conformational flexibility due to the loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces, which led to a decreased protease grip on... (More)
3C protease of Coxsackievirus B3 (CVB3) plays an essential role in the viral replication cycle, and therefore, emerged as an attractive therapeutic target for the treatment of human diseases caused by CVB3 infection. In this study, we report the first account of the molecular impact of the T68A/N126Y double mutant (MutantBound) using an integrated computational approach. Molecular dynamics simulation and post-dynamics binding free energy, principal component analysis (PCA), hydrogen bond occupancy, SASA, Rg and RMSF confirm that T68A/N126Y instigated an increased conformational flexibility due to the loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces, which led to a decreased protease grip on the ligand (). The double mutations triggered a distortion orientation of in the active site and decreases the binding energy, ΔGbind (∼3 kcal mol(-1)), compared to the wild type (WildBound). The van der Waals and electrostatic energy contributions coming from residues 68 and 126 are lower for MutantBound when compared with WildBound. In addition, variation in the overall enzyme motion as evident from the PCA, distorted hydrogen bonding network and loss of protein-ligand interactions resulted in a loss of inhibitor efficiency. The comprehensive molecular insight gained from this study should be of great importance in understanding the drug resistance against CVB3 3C protease; also, it will assist in the designing of novel Coxsackievirus B3 inhibitors with high ligand efficacy on resistant strains. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular BioSystems
volume
11
issue
8
pages
2303 - 2311
publisher
Royal Society of Chemistry
external identifiers
  • pmid:26077945
  • wos:000358024000021
  • scopus:84953638639
ISSN
1742-2051
DOI
10.1039/c5mb00262a
language
English
LU publication?
yes
id
86999620-ebf5-4309-87f5-1d0b7f8db64b (old id 7485853)
date added to LUP
2015-07-09 13:02:33
date last changed
2017-08-27 03:26:26
@article{86999620-ebf5-4309-87f5-1d0b7f8db64b,
  abstract     = {3C protease of Coxsackievirus B3 (CVB3) plays an essential role in the viral replication cycle, and therefore, emerged as an attractive therapeutic target for the treatment of human diseases caused by CVB3 infection. In this study, we report the first account of the molecular impact of the T68A/N126Y double mutant (MutantBound) using an integrated computational approach. Molecular dynamics simulation and post-dynamics binding free energy, principal component analysis (PCA), hydrogen bond occupancy, SASA, Rg and RMSF confirm that T68A/N126Y instigated an increased conformational flexibility due to the loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces, which led to a decreased protease grip on the ligand (). The double mutations triggered a distortion orientation of in the active site and decreases the binding energy, ΔGbind (∼3 kcal mol(-1)), compared to the wild type (WildBound). The van der Waals and electrostatic energy contributions coming from residues 68 and 126 are lower for MutantBound when compared with WildBound. In addition, variation in the overall enzyme motion as evident from the PCA, distorted hydrogen bonding network and loss of protein-ligand interactions resulted in a loss of inhibitor efficiency. The comprehensive molecular insight gained from this study should be of great importance in understanding the drug resistance against CVB3 3C protease; also, it will assist in the designing of novel Coxsackievirus B3 inhibitors with high ligand efficacy on resistant strains.},
  author       = {Bhakat, Soumendranath},
  issn         = {1742-2051},
  language     = {eng},
  number       = {8},
  pages        = {2303--2311},
  publisher    = {Royal Society of Chemistry},
  series       = {Molecular BioSystems},
  title        = {Effect of T68A/N126Y mutations on the conformational and ligand binding landscape of Coxsackievirus B3 3C protease.},
  url          = {http://dx.doi.org/10.1039/c5mb00262a},
  volume       = {11},
  year         = {2015},
}