Abstract
The interaction of HIV-1 trans-activator protein Tat with its cognate trans-activation response element (TAR) RNA is critical for viral transcription and replication. Therefore, it has long been considered as an attractive target for the development of antiviral compounds. Recently, the conformationally constrained cyclic peptide mimetics of Tat have been tested to be a promising family of lead peptides. Here, we focused on two representative cyclic peptides termed as L-22 and KP-Z-41, both of which exhibit excellent inhibitory potency against Tat and TAR interaction. By means of molecular dynamics simulations, we obtained a detailed picture of the interactions between them and HIV-1 TAR RNA. In results, it is found that the binding modes of the two cyclic peptides to TAR RNA are almost identical at or near the bulge regions, whereas the binding interfaces at the apical loop exhibit large conformational heterogeneity. In addition, it is revealed that electrostatic interaction energy contributes much more to KP-Z-41 complex formation than to L-22 complex, which is the main source of energy that results in a higher binding affinity of KP-Z-41 over-22 for TAR RNA. Furthermore, we identified a conserved motif RRK (Arg-Arg-Lys) that is shown to be essential for specific binding of this class of cyclic peptides to TAR RNA. This work can provide a useful insight into the design and modification of cyclic peptide inhibitors targeting the association of HIV-1 Tat and TAR RNA.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.