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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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Per-residue differential in ΔEelec term for inhibitor C34 of wild type and N43D mutant (kcal/mol).
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pone-0111923-g005: Per-residue differential in ΔEelec term for inhibitor C34 of wild type and N43D mutant (kcal/mol).

Mentions: Energy decomposition enables us to observe the energetic contribution of every residue in the receptor to binding with C34. In order to identify the key residues which are important for association, the free energy decomposition based on residues was performed through MM-GBSA method. Per-residue changes in ΔEelec term were computed both in wild type and N43D mutant models. As shown in Fig. 5, residue D43 is located near all four glutamic residues of C34, thus may lead to repulsion between negatively charged residues and result in conformation changes and dramatic energies loses. Especially for residue E137, great energy losses were found from either our results (Fig. 5) or other studies [17], [32].


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)

Per-residue differential in ΔEelec term for inhibitor C34 of wild type and N43D mutant (kcal/mol).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111923-g005: Per-residue differential in ΔEelec term for inhibitor C34 of wild type and N43D mutant (kcal/mol).
Mentions: Energy decomposition enables us to observe the energetic contribution of every residue in the receptor to binding with C34. In order to identify the key residues which are important for association, the free energy decomposition based on residues was performed through MM-GBSA method. Per-residue changes in ΔEelec term were computed both in wild type and N43D mutant models. As shown in Fig. 5, residue D43 is located near all four glutamic residues of C34, thus may lead to repulsion between negatively charged residues and result in conformation changes and dramatic energies loses. Especially for residue E137, great energy losses were found from either our results (Fig. 5) or other studies [17], [32].

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