Chem Biol Drug Des
Shandong Academy of Pharmaceutical Sciences, Jinan, China.
Published: July 2019
The respiratory syncytial virus fusion (RSV-F) protein is a primary target for vaccine and drug development against respiratory infection and pediatric pneumonia. The RSV-F core forms a trimer-of-hairpins (TOH) motif in postfusion conformation, which is characterized by a six-helix bundle (6HB) where the three N-terminal HRn helices define a central coiled-coil, while three C-terminal HRc helices pack on the coiled-coil surface in an antiparallel manner. Here, one tightly packed HRn-HRc helix-helix interaction is stripped from the 6HB, which represents the minimum unit of RSV-F TOH motif. The helix-helix interaction sequence can be truncated to derive a core binding region (CBR) that covers intense nonbonded interactions across the interaction interface. Dynamics simulation and energetics analysis reveal that the CBR HRc peptide has a large flexibility and intrinsic disorder in unbound free state, which would incur a considerable entropy penalty upon its binding to CBR NRn peptide. Two strategies are described to constrain the HRc peptide conformation. First, the four non-interfacial residues of HRc peptide are artificially substituted with new amino acid combinations of high helical propensity and, second, the helical conformation of wild-type and mutant HRc peptides is stabilized by adding an all-hydrocarbon bridge across two spatially vicinal, non-interfacial residues 503 (i) and 507 (i + 4). Free energy calculation and fluorescence-based assay confirm that the substitution and stapling can effectively improve the binding affinity of CBR HRn-HRc interaction.
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