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Possible Computational Evidence for Enhanced α-Helix in Modified CYFIP1-derived Peptides

posted Dec 7, 2017, 11:03 AM by Megan Wang   [ updated Dec 8, 2017, 8:30 AM by Emilio Gallicchio ]

Dysregulation of the eukaryotic translation initiation factor (eIf4E) has been shown to exist in Fragile X Syndrome, a leading cause of intellectual disabilities such as autism. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) plays a key regulatory role in repressing associated mRNA translation by binding to eIF4E. A crucial secondary structure element in the interactions between a CYFIP1-derived peptide (CYFIP1p) and eIF4E is the α-helix, and as a consequence, improving the persistence of α-helicity of the peptide could lead to improved binding efficiency. In our study, we made computer-aided chemical modifications in an effort to further stabilize the α-helix structures of peptides derived from wild-type CYFIP1p. Our findings suggest the addition of a staple comprised of alkyls or an aromatic ring has no significant impact on the secondary structure elements of the CYFIP1-derived peptides. However, modifications comprised of a long chemical staple combined with a mutation from serine to alanine resulted in improved α-helix stability and thus, exhibited a potential for enhanced binding efficiency. 

Snapshot of the trajectory for a CYFIP1-derived peptide exhibiting α-helix fold.

Possible Computational Evidence for Enhanced α-Helix in Modified CYFIP1-derived Peptides.docx


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