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. (c) 2007 Wiley Periodicals, Inc.