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Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.

Kramer M, Halleran D, Rahman M, Iqbal M, Anwar MI, Anwar MI, Sabet S, Ackad E, Yousef MS, Yousef M - PLoS ONE (2014)

Bottom Line: The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease.The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state.These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Edwardsville, Illinois, United States of America.

ABSTRACT
The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes 3 and 4, dominant in developing countries, are resistant to a number of these drugs and little progress has been made towards understanding the structural basis of their drug resistivity. We have previously developed a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active sites of the NS3 proteases of HCV-1b and 4a in relation to their catalytic activity and drug susceptibility. Here, we improved the methodology, extended the analysis to include genotype 3a (predominant in South Asia including Pakistan), and compared the results of the three genotypes (1b, 3a and 4a). The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease. The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state. These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.

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Related in: MedlinePlus

Dynamics behavior within the catalytic triad site of the threading models (HCV-4a, blue and HCV-3a, red) and the template (HCV-1b, green) proteases.The distance distribution profiles between Oδ2 of residues D81 and Nδ1 of H57 (a) and between Oγ of residue S139 and Nε2 of residue H57 (b), during the stimulation. Orange and brown arrows indicate the selected distances in the rigid structures of both the models (HCV-4a, d and HCV-3a, e) and the template (HCV-1b, c)
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pone-0104425-g003: Dynamics behavior within the catalytic triad site of the threading models (HCV-4a, blue and HCV-3a, red) and the template (HCV-1b, green) proteases.The distance distribution profiles between Oδ2 of residues D81 and Nδ1 of H57 (a) and between Oγ of residue S139 and Nε2 of residue H57 (b), during the stimulation. Orange and brown arrows indicate the selected distances in the rigid structures of both the models (HCV-4a, d and HCV-3a, e) and the template (HCV-1b, c)

Mentions: Locally, molecular dynamics simulations revealed a strain-dependent, gradually divergent dynamics behavior within the catalytic triad region, with HCV-1b being the most stable, the HCV-4a the most divergent and HCV-3a representing an intermediate state, (figures 2, 3 and 4). These dynamic differences seem to correlate well with the differences in catalytic activities and drug susceptibilities to Telaprevir seen in the three genotypes [2], [25]. This result strongly suggests that the local dynamics within the triad region in the NS3 protease could be used as a direct predictive measure for HCV pan-genotype drug susceptibilities.


Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.

Kramer M, Halleran D, Rahman M, Iqbal M, Anwar MI, Anwar MI, Sabet S, Ackad E, Yousef MS, Yousef M - PLoS ONE (2014)

Dynamics behavior within the catalytic triad site of the threading models (HCV-4a, blue and HCV-3a, red) and the template (HCV-1b, green) proteases.The distance distribution profiles between Oδ2 of residues D81 and Nδ1 of H57 (a) and between Oγ of residue S139 and Nε2 of residue H57 (b), during the stimulation. Orange and brown arrows indicate the selected distances in the rigid structures of both the models (HCV-4a, d and HCV-3a, e) and the template (HCV-1b, c)
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128671&req=5

pone-0104425-g003: Dynamics behavior within the catalytic triad site of the threading models (HCV-4a, blue and HCV-3a, red) and the template (HCV-1b, green) proteases.The distance distribution profiles between Oδ2 of residues D81 and Nδ1 of H57 (a) and between Oγ of residue S139 and Nε2 of residue H57 (b), during the stimulation. Orange and brown arrows indicate the selected distances in the rigid structures of both the models (HCV-4a, d and HCV-3a, e) and the template (HCV-1b, c)
Mentions: Locally, molecular dynamics simulations revealed a strain-dependent, gradually divergent dynamics behavior within the catalytic triad region, with HCV-1b being the most stable, the HCV-4a the most divergent and HCV-3a representing an intermediate state, (figures 2, 3 and 4). These dynamic differences seem to correlate well with the differences in catalytic activities and drug susceptibilities to Telaprevir seen in the three genotypes [2], [25]. This result strongly suggests that the local dynamics within the triad region in the NS3 protease could be used as a direct predictive measure for HCV pan-genotype drug susceptibilities.

Bottom Line: The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease.The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state.These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Edwardsville, Illinois, United States of America.

ABSTRACT
The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes 3 and 4, dominant in developing countries, are resistant to a number of these drugs and little progress has been made towards understanding the structural basis of their drug resistivity. We have previously developed a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active sites of the NS3 proteases of HCV-1b and 4a in relation to their catalytic activity and drug susceptibility. Here, we improved the methodology, extended the analysis to include genotype 3a (predominant in South Asia including Pakistan), and compared the results of the three genotypes (1b, 3a and 4a). The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease. The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state. These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.

Show MeSH
Related in: MedlinePlus