Molecular modeling and rational design of hydrocarbon-stapled/halogenated helical peptides targeting CETP self-binding site: Therapeutic implication for atherosclerosis

• Published in: Journal of molecular graphics & modelling 2020-01, Vol.94, p.107455-107455, Article 107455
• Main Authors: Zhu, Jian, Wei, Sen, Huang, Linchen, Zhao, Qi, Zhu, Haichao, Zhang, Anwei
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Cholesteryl ester transfer protein; Conformational flexibility; Hydrocarbon stapling; Molecular modeling; Self-binding peptide
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2019.107455

The human plasma cholesteryl ester transfer protein (CETP) collects triglycerides from very-/low-density lipoproteins (V/LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), which has recognized as an important therapeutic target for atherosclerosis. The protein has a C-terminal amphipathic α-helix that serves as self-binding peptide to fulfill biological function by dynamically binding to/unbinding from its cognate site (termed self-binding site) in the same protein. Previously, we successfully derived and halogenated the helical peptide to competitively disrupt the self-binding behavior of CETP C-terminal tail. However, the halogenated peptides have only a limited affinity increase as compared to native helical peptide (∼3-fold), thus exhibiting only a moderate competitive potency. Here, instead of optimizing the direct intermolecular interaction of peptide with CETP self-binding site we attempt to further improve the peptide competitive potency by reducing its conformational flexibility with hydrocarbon-stapling technique. Computational analysis reveals that the helical peptide has large intrinsic disorder in unbound free state, which would incur a considerable entropy penalty upon rebinding to the self-binding site. All-hydrocarbon bridge is designed and optimized on native and halogenated peptides in terms of the helical pattern and binding mode of self-binding peptide. Dynamics simulation and circular dichroism indicate that the stapling can considerably reduce peptide disorder in free state. Energetics calculation and fluorescence assay conform that the binding affinity of stapled/halogenated peptides is improved substantially (by > 5-fold), thus exhibiting an effective competition potency with native peptide for the self-binding site. Structural examination suggests that the binding modes and nonbonded interactions of native and halogenated peptides are not influenced essentially due to the stapling. [Display omitted] •A helical peptide derived from the C-terminal tail of CETP protein exhibits self-binding behavior to the protein.•The peptide possesses large flexibility in unbound state, which is unfavorable for its binding to CETP.•All-hydrocarbon bridge is stapled on native peptide and its halogenated version to constrain helical conformation.•Stapled peptides exhibit higher affinity to CETP and stronger competition potency with native peptide.