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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 (N43D/S138A double mutant minus N43D single mutant) footprints for receptor (kcal/mol).
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pone-0111923-g008: Per-residue differential (N43D/S138A double mutant minus N43D single mutant) footprints for receptor (kcal/mol).

Mentions: In order to gain extra insight into the mechanism of the fact that double mutant has greater binding energy than single mutant, and to determine hotspot regions within binding site and specific amino acids which play important roles for binding, a footprints analysis for energetic contributions is performed (Fig. 8). As displayed in Figure 4, CHR (C34) of N43D/S138A double mutant binds to NHR without structure torsion, CHR has inclined to NHR-B chain comparing with single mutant. It makes CHR of double mutant has more interactions with NHR-B, as the result, residues before S133 of CHR may make more interactions with chain NHR-B and residues after S133 may have more interactions with NHR-A (Fig. 8), with more interactions, CHR binds with receptor more stronger. Because the contribution of van der Waals interaction is the main difference between single mutant and double mutant, the footprints analysis for van der Waals interaction is explored, Fig. 9 showed the key residues in CHR (C34) which displayed great changes between two systems. It reveals that W117, W120, I124, Y127, T128, I131, L134, I135, A138, Q141 and Q142 of ligand in N43D/S138A double mutant make strong interactions with receptor. But for single mutant system, interactions for I135, A138, Q139, Q141 and Q142 are relatively weak. It had be reported that van der Waals interactions would be negligible when the distance between molecular is larger than 2.5 σ [35]. To visualize the different van der Waals contribution of these residues in two systems, the structures of inhibitor and its contact residues are determined with the default cutoff of 8.5 Å, respectively. We examined the contact residues of E137, S138A, Q139, Q141 and Q142 for two systems with cutoff of 8.5 Å. (Fig. 10a and Fig. 10b show interactions between NHR and these residues of N43D and N43D/S138A systems, respectively). Compared with single mutant, the binding mode of N43D/S138A is much favorable for binding in this region, which leads to enhanced van der Waals interactions. Fig. 10a and Fig. 10b shows that the binding interface of double mutant has induced more profit of hydrophobic interaction. It indicated that compensatory mutation S138A may enhance the binding stabilization between NHR and CHR through additional hydrophobic contacts, as many studies mentioned [36]. The crystal structure of 6HB has shown that the S138 side chain interacts with Q40 and L45 [17], [23]. We examined the structure of N43D single mutant system and found that S138 could contact with L45 and D43. Some researches suggested that A138 contacts with hydrophobic cavity formed with residues N43, L44, L45, A47 and I48 [17], in our research, the compensatory mutant A138 is optimal for binding into hydrophobic cavity formed by Q40, L44, L45, A47 and I48 (Fig. 11). Therefore, we suggest that the different behavior of C34 in two systems induce huge energetic changes, the binding mode of double mutant results in the favorable binding near the A138. This slight structure difference between single mutant and double mutant has caused these more profit of interactions at interface. By this line of reasoning, the compensatory mutation S138A (yielding N43D/S138A) induced the greater hydrophobic interactions between NHR and CHR, and may led to greater resistance to drug than the single N43D escape mutant.


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 (N43D/S138A double mutant minus N43D single mutant) footprints for receptor (kcal/mol).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111923-g008: Per-residue differential (N43D/S138A double mutant minus N43D single mutant) footprints for receptor (kcal/mol).
Mentions: In order to gain extra insight into the mechanism of the fact that double mutant has greater binding energy than single mutant, and to determine hotspot regions within binding site and specific amino acids which play important roles for binding, a footprints analysis for energetic contributions is performed (Fig. 8). As displayed in Figure 4, CHR (C34) of N43D/S138A double mutant binds to NHR without structure torsion, CHR has inclined to NHR-B chain comparing with single mutant. It makes CHR of double mutant has more interactions with NHR-B, as the result, residues before S133 of CHR may make more interactions with chain NHR-B and residues after S133 may have more interactions with NHR-A (Fig. 8), with more interactions, CHR binds with receptor more stronger. Because the contribution of van der Waals interaction is the main difference between single mutant and double mutant, the footprints analysis for van der Waals interaction is explored, Fig. 9 showed the key residues in CHR (C34) which displayed great changes between two systems. It reveals that W117, W120, I124, Y127, T128, I131, L134, I135, A138, Q141 and Q142 of ligand in N43D/S138A double mutant make strong interactions with receptor. But for single mutant system, interactions for I135, A138, Q139, Q141 and Q142 are relatively weak. It had be reported that van der Waals interactions would be negligible when the distance between molecular is larger than 2.5 σ [35]. To visualize the different van der Waals contribution of these residues in two systems, the structures of inhibitor and its contact residues are determined with the default cutoff of 8.5 Å, respectively. We examined the contact residues of E137, S138A, Q139, Q141 and Q142 for two systems with cutoff of 8.5 Å. (Fig. 10a and Fig. 10b show interactions between NHR and these residues of N43D and N43D/S138A systems, respectively). Compared with single mutant, the binding mode of N43D/S138A is much favorable for binding in this region, which leads to enhanced van der Waals interactions. Fig. 10a and Fig. 10b shows that the binding interface of double mutant has induced more profit of hydrophobic interaction. It indicated that compensatory mutation S138A may enhance the binding stabilization between NHR and CHR through additional hydrophobic contacts, as many studies mentioned [36]. The crystal structure of 6HB has shown that the S138 side chain interacts with Q40 and L45 [17], [23]. We examined the structure of N43D single mutant system and found that S138 could contact with L45 and D43. Some researches suggested that A138 contacts with hydrophobic cavity formed with residues N43, L44, L45, A47 and I48 [17], in our research, the compensatory mutant A138 is optimal for binding into hydrophobic cavity formed by Q40, L44, L45, A47 and I48 (Fig. 11). Therefore, we suggest that the different behavior of C34 in two systems induce huge energetic changes, the binding mode of double mutant results in the favorable binding near the A138. This slight structure difference between single mutant and double mutant has caused these more profit of interactions at interface. By this line of reasoning, the compensatory mutation S138A (yielding N43D/S138A) induced the greater hydrophobic interactions between NHR and CHR, and may led to greater resistance to drug than the single N43D escape mutant.

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