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Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations

View Article: PubMed Central - PubMed

ABSTRACT

Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.

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Related in: MedlinePlus

Molecular Dynamic simulations of 6-HBs.(A) Variance of the average Cα-Cα distance between a C-terminal residue of CP-IDL and all residues of an adjacent NHR helix during one simulation run of 60 ns performed on an N43-L6-CP-IDL 6HB model. (B) Lengths of the hydrogen bonds responsible for the α-helical conformation of the IDL tails in a N36-L6-CP-IDL 6HB model. (C) Contributions of individual IDL tails to the buried surface area between CP-IDL and NHR trimer in an N43-L6-CP-IDL 6HB model during one simulation run of 60 ns, as well as their sum. See methods for details.
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f4: Molecular Dynamic simulations of 6-HBs.(A) Variance of the average Cα-Cα distance between a C-terminal residue of CP-IDL and all residues of an adjacent NHR helix during one simulation run of 60 ns performed on an N43-L6-CP-IDL 6HB model. (B) Lengths of the hydrogen bonds responsible for the α-helical conformation of the IDL tails in a N36-L6-CP-IDL 6HB model. (C) Contributions of individual IDL tails to the buried surface area between CP-IDL and NHR trimer in an N43-L6-CP-IDL 6HB model during one simulation run of 60 ns, as well as their sum. See methods for details.

Mentions: To assess the stabilities of two IDL conformations, molecular dynamics (MD) simulations were performed on two 6-HB models from the crystal structures of N36- and N43-L6-CP-IDL, respectively, as well as isolated CP-IDL peptides in the two structures. In 2 runs of 60 ns we conducted, the hook-like structure of the IDL tails was generally retained in an N43-L6-CP-IDL 6HB. The positions of 6 C-terminal residues were assessed by calculating the variance of their distances to the NHR within the same fusion peptide (average Cα-Cα distance). As shown in Fig. 4A, residue Ile654 of IDL tail was as tightly fixed as the residues prior to it, while the other two residues of IDL tail, Asp655 and Leu656, were more flexible. However, the interface area between a hook-like IDL tail and an NHR trimer was roughly stable in the range of 150~300 Å2, contributing 12~25% of the interface between CP-IDL and NHR (Fig. 4B). Interestingly, the total interface area of three IDL tails in the same 6-HB is more stable than individual tails, possessing a contribution of 15~22% (Fig. 4B). As for the IDL tails in an N36-L6-CP-IDL 6HB, analysis of the hydrogen-bonds responsible for the α-helical conformation of the C-terminus showed that the helical conformation could be stabilized during 2 runs of 115 ns (Fig. 4C). However, without the presence of NHR trimer, neither helical nor hook-like structure of the IDL tail could be maintained for more than 10 ns in the 4 runs we performed on each peptide (Movie S1). In conclusion, MD simulations indicated that the IDL tail in a separated CP-IDL peptide tend to bear a disordered conformation, which will be altered to a stable helical or hook-like structure when binding to short or long NHR helices, respectively.


Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations
Molecular Dynamic simulations of 6-HBs.(A) Variance of the average Cα-Cα distance between a C-terminal residue of CP-IDL and all residues of an adjacent NHR helix during one simulation run of 60 ns performed on an N43-L6-CP-IDL 6HB model. (B) Lengths of the hydrogen bonds responsible for the α-helical conformation of the IDL tails in a N36-L6-CP-IDL 6HB model. (C) Contributions of individual IDL tails to the buried surface area between CP-IDL and NHR trimer in an N43-L6-CP-IDL 6HB model during one simulation run of 60 ns, as well as their sum. See methods for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036048&req=5

f4: Molecular Dynamic simulations of 6-HBs.(A) Variance of the average Cα-Cα distance between a C-terminal residue of CP-IDL and all residues of an adjacent NHR helix during one simulation run of 60 ns performed on an N43-L6-CP-IDL 6HB model. (B) Lengths of the hydrogen bonds responsible for the α-helical conformation of the IDL tails in a N36-L6-CP-IDL 6HB model. (C) Contributions of individual IDL tails to the buried surface area between CP-IDL and NHR trimer in an N43-L6-CP-IDL 6HB model during one simulation run of 60 ns, as well as their sum. See methods for details.
Mentions: To assess the stabilities of two IDL conformations, molecular dynamics (MD) simulations were performed on two 6-HB models from the crystal structures of N36- and N43-L6-CP-IDL, respectively, as well as isolated CP-IDL peptides in the two structures. In 2 runs of 60 ns we conducted, the hook-like structure of the IDL tails was generally retained in an N43-L6-CP-IDL 6HB. The positions of 6 C-terminal residues were assessed by calculating the variance of their distances to the NHR within the same fusion peptide (average Cα-Cα distance). As shown in Fig. 4A, residue Ile654 of IDL tail was as tightly fixed as the residues prior to it, while the other two residues of IDL tail, Asp655 and Leu656, were more flexible. However, the interface area between a hook-like IDL tail and an NHR trimer was roughly stable in the range of 150~300 Å2, contributing 12~25% of the interface between CP-IDL and NHR (Fig. 4B). Interestingly, the total interface area of three IDL tails in the same 6-HB is more stable than individual tails, possessing a contribution of 15~22% (Fig. 4B). As for the IDL tails in an N36-L6-CP-IDL 6HB, analysis of the hydrogen-bonds responsible for the α-helical conformation of the C-terminus showed that the helical conformation could be stabilized during 2 runs of 115 ns (Fig. 4C). However, without the presence of NHR trimer, neither helical nor hook-like structure of the IDL tail could be maintained for more than 10 ns in the 4 runs we performed on each peptide (Movie S1). In conclusion, MD simulations indicated that the IDL tail in a separated CP-IDL peptide tend to bear a disordered conformation, which will be altered to a stable helical or hook-like structure when binding to short or long NHR helices, respectively.

View Article: PubMed Central - PubMed

ABSTRACT

Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.

No MeSH data available.


Related in: MedlinePlus