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Molecular dynamics studies of the inhibitor C34 binding to the wild-type and mutant HIV-1 gp41: inhibitory and drug resistant mechanism.

Ma X, Tan J, Su M, Li C, Zhang X, Wang C - PLoS ONE (2014)

Bottom Line: Mutations on NHR (N-terminal heptad repeat) associated with resistance to fusion inhibitor were observed.Through the comparative analysis of MD results of the N43D mutant and the N43D/S138A mutant, we found that CHR with S138A mutation shown more favorable affinity to NHR.Compelling differences in structures have been observed for these two mutants, particularly in the binding modes and in the hydrophobic interactions of the CHR (C34) located near the hydrophobic groove of the NHR.

View Article: PubMed Central - PubMed

Affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China.

ABSTRACT
Mutations on NHR (N-terminal heptad repeat) associated with resistance to fusion inhibitor were observed. In addition, mutations on CHR (C-terminal heptad repeat) accompanied NHR mutations of gp41 are noted in many cases, like N43D/S138A double mutation. In this work, we explored the drug resistant mechanism of N43D mutation and the role of S138A second mutation in drug resistance. The binding modes of the wild type gp41 and the two mutants, N43D and N43D/S138A, with the HIV-1 fusion inhibitor C34, a 34-residue peptide mimicking CHR of gp41, were carried out by using molecular dynamics simulations. Based on the MD simulations, N43D mutation affects not only the stability of C34 binding, but also the binding energy of the inhibitor C34. Because N43D mutation may also affect the stable conformation of 6-HB, we introduced S138A second mutation into CHR of gp41 and determined the impact of this mutation. Through the comparative analysis of MD results of the N43D mutant and the N43D/S138A mutant, we found that CHR with S138A mutation shown more favorable affinity to NHR. Compelling differences in structures have been observed for these two mutants, particularly in the binding modes and in the hydrophobic interactions of the CHR (C34) located near the hydrophobic groove of the NHR. Because the conformational stability of 6-HB is important to HIV-1 infection, we suggested a hypothetical mechanism for the drug resistance: N43D single mutation not only impact the binding of inhibitor, but also affect the affinity between NHR and CHR of gp41, thus may reduce the rate of membrane fusion; compensatory mutation S138A would induce greater hydrophobic interactions between NHR and CHR, and render the CHR more compatible to NHR than inhibitors.

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Comparisons of backbone atoms RMSF in inhibitor C34 of wild type and N43D mutant.
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pone-0111923-g002: Comparisons of backbone atoms RMSF in inhibitor C34 of wild type and N43D mutant.

Mentions: To track the extent of variation of individual residues of inhibitor C34 in complex, the per-residue root-mean-square fluctuations (RMSFs) of backbone atoms were computed, over the 15 ns MD simulation of inhibitor C34 in N43D mutation, we observed the 137–150 peptide of the N43D mutation type shows higher RMS fluctuations than that found in WT system. (see Fig. 2). Upon examination, we found that this is mainly owing to the charged mutation N43D, in the wild type (WT) residues in this region would interact with Asn43 of HR1 and form the Hydrogen bonds, but in the mutant type (N43D), interactions are found to be unconspicuous, the substitution of Asp for Asn breaks these interactions. The structure of these two models display different binding patterns, compare with WT system, in the mutation type, this domain of the ligand bind with receptor in a stance of torsion indicating that N43D mutation would affect the binding.


Molecular dynamics studies of the inhibitor C34 binding to the wild-type and mutant HIV-1 gp41: inhibitory and drug resistant mechanism.

Ma X, Tan J, Su M, Li C, Zhang X, Wang C - PLoS ONE (2014)

Comparisons of backbone atoms RMSF in inhibitor C34 of wild type and N43D mutant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230944&req=5

pone-0111923-g002: Comparisons of backbone atoms RMSF in inhibitor C34 of wild type and N43D mutant.
Mentions: To track the extent of variation of individual residues of inhibitor C34 in complex, the per-residue root-mean-square fluctuations (RMSFs) of backbone atoms were computed, over the 15 ns MD simulation of inhibitor C34 in N43D mutation, we observed the 137–150 peptide of the N43D mutation type shows higher RMS fluctuations than that found in WT system. (see Fig. 2). Upon examination, we found that this is mainly owing to the charged mutation N43D, in the wild type (WT) residues in this region would interact with Asn43 of HR1 and form the Hydrogen bonds, but in the mutant type (N43D), interactions are found to be unconspicuous, the substitution of Asp for Asn breaks these interactions. The structure of these two models display different binding patterns, compare with WT system, in the mutation type, this domain of the ligand bind with receptor in a stance of torsion indicating that N43D mutation would affect the binding.

Bottom Line: Mutations on NHR (N-terminal heptad repeat) associated with resistance to fusion inhibitor were observed.Through the comparative analysis of MD results of the N43D mutant and the N43D/S138A mutant, we found that CHR with S138A mutation shown more favorable affinity to NHR.Compelling differences in structures have been observed for these two mutants, particularly in the binding modes and in the hydrophobic interactions of the CHR (C34) located near the hydrophobic groove of the NHR.

View Article: PubMed Central - PubMed

Affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China.

ABSTRACT
Mutations on NHR (N-terminal heptad repeat) associated with resistance to fusion inhibitor were observed. In addition, mutations on CHR (C-terminal heptad repeat) accompanied NHR mutations of gp41 are noted in many cases, like N43D/S138A double mutation. In this work, we explored the drug resistant mechanism of N43D mutation and the role of S138A second mutation in drug resistance. The binding modes of the wild type gp41 and the two mutants, N43D and N43D/S138A, with the HIV-1 fusion inhibitor C34, a 34-residue peptide mimicking CHR of gp41, were carried out by using molecular dynamics simulations. Based on the MD simulations, N43D mutation affects not only the stability of C34 binding, but also the binding energy of the inhibitor C34. Because N43D mutation may also affect the stable conformation of 6-HB, we introduced S138A second mutation into CHR of gp41 and determined the impact of this mutation. Through the comparative analysis of MD results of the N43D mutant and the N43D/S138A mutant, we found that CHR with S138A mutation shown more favorable affinity to NHR. Compelling differences in structures have been observed for these two mutants, particularly in the binding modes and in the hydrophobic interactions of the CHR (C34) located near the hydrophobic groove of the NHR. Because the conformational stability of 6-HB is important to HIV-1 infection, we suggested a hypothetical mechanism for the drug resistance: N43D single mutation not only impact the binding of inhibitor, but also affect the affinity between NHR and CHR of gp41, thus may reduce the rate of membrane fusion; compensatory mutation S138A would induce greater hydrophobic interactions between NHR and CHR, and render the CHR more compatible to NHR than inhibitors.

Show MeSH
Related in: MedlinePlus