A Natural Interruption Displays Higher Global Stability and Local Conformational Flexibility than a Similar Gly Mutation Sequence in Collagen Mimic Peptides.
Natural interruptions in the repeating (Gly-X-Y)n amino acid sequence pattern are found normally in triple helix domains of all nonfibrillar collagens, while any Gly substitution in fibrillar collagens leads to pathological conditions. As revealed by our sequence analysis, two peptides, one modeling a natural G5G interruption (POALO) and the other one mimicking a pathological Gly-to-Ala substitution (LOAPO), are designed. Circular dichroism (CD), NMR, and computational simulation studies have discovered significant differences in stability, conformation, and folding between the two peptides. Compared with the Gly substitution sequence, the natural interruption maintains higher stability, higher triple helix content, and a higher folding rate while introducing more alterations in local triple helical conformation in terms of dihedral angles and hydrogen bonding. The conserved hydrophobic residues at the specific sites of interruptions may provide functional constraints for higher-order assembly as well as biomolecular interactions. These results suggest a molecular basis of different biological roles of natural interruptions and Gly substitutions and may guide the design of collagen mimic peptides containing functional natural interruptions.
Xiuxia
X
Sun
Yalin
Y
Chai
Qianqian
Q
Wang
Huanxiang
H
Liu
College of Chemistry and Molecular Sciences, Wuhan University , Wuhan 430072, P. R. China.
Shaoru
S
Wang
Jianxi
J
Xiao
D000409:Alanine / Q000737:chemistry / Q000235:genetics; D019943:Amino Acid Substitution; D002942:Circular Dichroism; D003094:Collagen / Q000737:chemistry* / Q000235:genetics; D005998:Glycine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D055550:Protein Stability; D017433:Protein Structure, Secondary
D010455:Peptides; D003094:Collagen; D000409:Alanine; D005998:Glycine