Structural highlights
Publication Abstract from PubMedWe report a new method for preorganization of alpha/beta-peptide helices, based on the use of a dense array of acidic and basic side chains. Previously we have used cyclically constrained beta residues to promote alpha/beta-peptide helicity; here we show that an engineered ion pair array can be comparably effective, as indicated by mimicry of the CHR domain of HIV protein gp41. The new design is effective in biochemical and cell-based infectivity assays; however, the resulting alpha/beta-peptide is susceptible to proteolysis. This susceptibility was addressed via introduction of a few cyclic beta residues near the cleavage site, to produce the most stable, effective alpha/beta-peptide gp41 CHR analogue identified. Crystal structures of an alpha- and alpha/beta-peptide (each involved in a gp41-mimetic helix bundle) that contain the dense acid/base residue array manifest disorder in the ionic side chains, but there is little side-chain disorder in analogous alpha- and alpha/beta-peptide structures with a sparser ionic side-chain array. These observations suggest that dense arrays of complementary acidic and basic residues can provide conformational stabilization via Coulombic attractions that do not require entropically costly ordering of side chains. Enhancement of alpha-Helix Mimicry by an alpha/beta-Peptide Foldamer via Incorporation of a Dense Ionic Side-Chain Array.,Johnson LM, Mortenson DE, Yun HG, Horne WS, Ketas TJ, Lu M, Moore JP, Gellman SH J Am Chem Soc. 2012 Apr 23. PMID:22524614[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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