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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 binding free energies for two system.(a) Per-residue differential (wild type minus mutant) footprints for receptor (b) Per-residue differential (wild type minus mutant) footprints for C34 (kcal/mol).
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pone-0111923-g006: Per-residue differential in binding free energies for two system.(a) Per-residue differential (wild type minus mutant) footprints for receptor (b) Per-residue differential (wild type minus mutant) footprints for C34 (kcal/mol).

Mentions: Per-residue changes of binding energy in two systems are shown in Fig. 6, Per-residue differential (wild type minus mutant) footprints for receptor and ligand is shown. From Fig. 6, we can observe that in two systems (the wild type and N43D mutant), residues Q40, N/D43 and S138 have large differences for energetic contribution. As shown in Fig. 6, after the mutation N43D on NHR of gp41, Q40, N/D43 and S138 showed larger losses of energetic contribution. In fact, the energetic difference is related to the binding mode of ligand after the N43D mutation. Per-residue changes in van der Waals were computed. As shown in Fig. 7, the two curves for wild type and N43D mutant system are nearly superimoposable, except residues near the torsion. In Fig. 7, residues E137, S138, Q139, Q141 and Q142 show larger losses of van der Waals energy in N43D single mutant than wild type.


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 binding free energies for two system.(a) Per-residue differential (wild type minus mutant) footprints for receptor (b) Per-residue differential (wild type minus mutant) footprints for C34 (kcal/mol).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111923-g006: Per-residue differential in binding free energies for two system.(a) Per-residue differential (wild type minus mutant) footprints for receptor (b) Per-residue differential (wild type minus mutant) footprints for C34 (kcal/mol).
Mentions: Per-residue changes of binding energy in two systems are shown in Fig. 6, Per-residue differential (wild type minus mutant) footprints for receptor and ligand is shown. From Fig. 6, we can observe that in two systems (the wild type and N43D mutant), residues Q40, N/D43 and S138 have large differences for energetic contribution. As shown in Fig. 6, after the mutation N43D on NHR of gp41, Q40, N/D43 and S138 showed larger losses of energetic contribution. In fact, the energetic difference is related to the binding mode of ligand after the N43D mutation. Per-residue changes in van der Waals were computed. As shown in Fig. 7, the two curves for wild type and N43D mutant system are nearly superimoposable, except residues near the torsion. In Fig. 7, residues E137, S138, Q139, Q141 and Q142 show larger losses of van der Waals energy in N43D single mutant than wild type.

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