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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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Structures of wild type (white) and N43D mutant (blue).
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pone-0111923-g003: Structures of wild type (white) and N43D mutant (blue).

Mentions: Structures of two models are shown in Fig. 3, wild type and N43D mutant have displayed different binding patterns. Here, for convenience, NHR chains interacting with CHR (or C34) are represented with NHR-A and NHR-B. In wild type, C34 is compressed into α-helix along the inner trimeric core of the NHR of gp41, and located at the hydrophobic groove. The binding region in N43D mutant is similar to that found in WT, while the configuration of inhibitor C34 is different, in the N43D mutant, the single mutation would cause the structure torsion of C34. We observed the binding interface of C34 in complex structures, the binding site of residues from 137 to 145 of wild type is deep inside the hydrophobic groove comparing with that in mutation type. In wild type, residues after E137 insert into the hydrophobic groove by interacting with NHR-B. However, in N43D mutant, structure torsion of inhibitor C34 would interfere with the orientation of these residues, the interaction involving these residues (residues after E137) and hydrophobic groove of NHR is changed, residues of C34 have more interactions with NHR-A.


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)

Structures of wild type (white) and N43D mutant (blue).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111923-g003: Structures of wild type (white) and N43D mutant (blue).
Mentions: Structures of two models are shown in Fig. 3, wild type and N43D mutant have displayed different binding patterns. Here, for convenience, NHR chains interacting with CHR (or C34) are represented with NHR-A and NHR-B. In wild type, C34 is compressed into α-helix along the inner trimeric core of the NHR of gp41, and located at the hydrophobic groove. The binding region in N43D mutant is similar to that found in WT, while the configuration of inhibitor C34 is different, in the N43D mutant, the single mutation would cause the structure torsion of C34. We observed the binding interface of C34 in complex structures, the binding site of residues from 137 to 145 of wild type is deep inside the hydrophobic groove comparing with that in mutation type. In wild type, residues after E137 insert into the hydrophobic groove by interacting with NHR-B. However, in N43D mutant, structure torsion of inhibitor C34 would interfere with the orientation of these residues, the interaction involving these residues (residues after E137) and hydrophobic groove of NHR is changed, residues of C34 have more interactions with NHR-A.

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