The design of synthetic structures that mimic large and noncontiguous regions of a protein surface remains an elusive goal.1 There has been considerable success in the field of small peptidomimeticsthat reproduce features of short peptides in extended2 or â-turn conformations. 3 However, much less progress has been made in the search for proteomimeticsor nonpeptide structures that mimic larger areas of the protein surface 4 such as an R-helix.5 This is remarkable given the ubiquitous role of R-helical regions in mediating protein -protein interactions. 6 The difficulty clearly lies in the large and elongated surface area that is presented by 2 -4 turns of anR-helix. One strategy involves the covalent or noncovalent stabilization of a 16 -20-mer peptide in a helical conformation either through side chain contacts, 7 end capping templation, 8 specific folding9 or use ofâ-peptides. 10 As part of our interest in helix surface recognition, 11,12we sought an entirely nonpeptidic scaffold that could be synthesized in a modular fashion and project side chain functionality with similar distance and angular relationships to those found in R-helices. We herein report a new family of proteomimetics , based on a functionalized terphenyl scaffold, that are structural mimics of two turns of the myosin light chain kinase R-helix and show functional analogy in binding with high affinity to calmodulin. In R-helix-protein complexes critical interactions are often found along one face of the helix, involving side chains from the i, i + 3, andi + 7 residues. 6 The relative positions of these groups in an all-AlaR-helix are shown in Figure 1 A -D and compared to the projection of substituents in a tris-functionalized 3,2 ′,2′′terphenyl derivative. 13 This is an attractive template for proteomimetic design due to the simplicity of the structure and the potential for an iterative synthesis. The alternating arrangement of i, i + 3, and i + 7 groups through two turns in the helix compares well with the 3,2 ′,2′′-substituents when the terphenyl is in a staggered conformation with dihedral angles of 68 ° and 36° between the phenyl rings. 14 In this easily accessible conformation, the three subsituents project from the terphenyl core with similar angular relationships and 4 -25% shorter distances than between thei, i + 3, andi + 7 â-carbons in anR-helix (Figure 1C and D). 15