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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.

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.

SUBMITTER: Ma X

PROVIDER: S-EPMC4230944 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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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 Xueting X Tan Jianjun J Su Min M Li Chunhua C Zhang Xiaoyi X Wang Cunxin C

PloS one 20141113 11

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 C ...[more]

PMID: 25393106

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Project description:In the present work, the binding of inhibitor TMC114 (darunavir) to wild-type (WT), single (I50V) as well as double (I50L/A71V) mutant HIV-proteases (HIV-pr) was investigated with all-atom molecular dynamics (MD) simulations as well as molecular mechanic-Poisson-Boltzmann surface area (MM-PBSA) calculation. For both the apo and complexed HIV-pr, many intriguing effects due to double mutant, I50L/A71V, are observed. For example, the flap-flap distance and the distance from the active site to the flap residues in the apo I50L/A71V-HIV-pr are smaller than those of WT- and I50V-HIV-pr, probably making the active site smaller in volume and closer movement of flaps. For the complexed HIV-pr with TMC114, the double mutant I50L/A71V shows a less curling of the flap tips and less flexibility than WT and the single mutant I50V. As for the other previous studies, the present results also show that the single mutant I50V decreases the binding affinity of I50V-HIV-pr to TMC, resulting in a drug resistance; whereas the double mutant I50L/A71V increases the binding affinity, and as a result of the stronger binding, the I50L/A71V may be well adapted by the TMC114. The energy decomposition analysis suggests that the increase of the binding for the double mutant I50L/A71V-HIV-pr can be mainly attributed to the increase in electrostatic energy by -5.52 kacl/mol and van der Waals by -0.42 kcal/mol, which are canceled out in part by the increase of polar solvation energy of 1.99 kcal/mol. The I50L/A71V mutant directly increases the binding affinity by approximately -0.88 (Ile50 to Leu50) and -0.90 (Ile50' to Leu50') kcal/mol, accounting 45% for the total gain of the binding affinity. Besides the direct effects from the residues Leu50 and Leu50', the residue Gly49' increases the binding affinity of I50L/A71V-HIV-pr to the inhibitor by -0.74 kcal/mol, to which the electrostatic interaction of Leu50's backbone contributes by -1.23 kcal/mol. Another two residues Ile84 and Ile47' also increase the binding affinity by -0.22 and -0.29 kcal/mol, respectively, which can be mainly attributed to van der Waals terms (ΔT(vdw) = -0.21 and -0.39 kcal/mol).

Dataset Information

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

Publications

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

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