Protein recognition motifs: design of peptidomimetics of helix surfaces.
Helices represent one of the most common recognition motifs in proteins. The design of nonpeptidic scaffolds, such as the 3,2',2''-tris-substituted terphenyl, that can imitate the side-chain orientation along one face of an alpha-helix potentially provides an effective means to modulate helix-recognition functions. Here, based on theoretical arguments, we described novel alpha-helix mimetics which are more effective than the terphenyl at constraining the aryl-aryl torsion angles to those associated with structures suitable for mimicking the alpha-helical twist for side-chain orientation and for superimposing the side chains of residues i, i + 3 or i + 4, i + 7 when compared with the alpha-beta side-chain vectors of the regular alpha-helix with an improved root mean square deviation (RMSD) of approximately 0.5 A. In addition, this study suggests that rotamer distributions around the C(alpha)--C(beta) bonds of these helix mimetics are similar to those of alpha-helices, except that these rotamer distributions show an approximately 60 degrees shift compared to those of alpha-helices when the mimetic axis is superimposed upon the helix axis. This change in rotamer orientation complicates mimicry of the helix surface.
Che
Ye
Y
Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. chey@nhlbi.nih.gov
Brooks
Bernard R
BR
Marshall
Garland R
GR
D020816:Amino Acid Motifs; D015195:Drug Design; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012399:Rotation; D013730:Terphenyl Compounds / Q000737:chemistry
D010455:Peptides; D013730:Terphenyl Compounds