Contributions of cation-π interactions to the collagen triple helix stability

Cation-pi interactions are found to be an important noncovalent force in proteins. Collagen is a right-handed triple helix composed of three left-handed PPII helices, in which (X-Y-Gly) repeats dominate in the sequence. Molecular modeling indicates that cation-pi interactions could be formed between the X and Y positions in adjacent collagen strands. Here, we used a host-guest peptide system: (Pro-Hyp-Gly)(3)-(Pro-Y-Gly-X-Hyp-Gly)-(Pro-Hyp-Gly)(3), where X is an aromatic residue and Y is a cationic residue, to study the cation-pi interaction in the collagen triple helix. Circular dichroism (CD) measurements and T-m, data analysis show that the cation-pi interactions involving Arg have a larger contribution to the conformational stability than do those involving Lys, and Trp forms a weaker cation-pi interaction with cationic residues than expected as a result of steric effects. The results also show that the formation of cation-pi interactions between Arg and Phe depends on their relative positions in the strand. Moreover, the fluorinated and methylated Phe substitutions show that an electron-withdrawing or electron-donating substituent on the aromatic ring can modulate its pi-electron density and the cation-pi interaction in collagen. Our data demonstrate that the cation-pi interaction could play an important role in stabilizing the collagen triple helix. (C) 2011 Elsevier Inc. All rights reserved.