Abstract
Human type III collagen has been suggested to play vital roles in a series of pathophysiological conditions. Sequence analysis among major fibril-forming collagens (types I, II, and III) revealed that Gly-Gly pairs are a distinct sequence feature in type III collagen. This motif occurs more than five times as often in type III compared to type I and II collagens. We used an integrated computational modeling and biophysical approach to analyze the glycine pair motifs to understand how they govern the structure of type III collagen at the molecular level. Triple helical peptides to model the regions of type III collagen containing GG motifs were used to analyze structural and thermodynamic effects of GG incorporation into the collagen sequence. We found that when amino acids adjacent to a GG motif are charged, the collagen adopts a more flexible, random conformation. The GG motif led to altered hydrogen bond patterns and decreased global melting temperatures of the triple helical peptides. The local entropic destabilization effect of the glycine pair helps explain the difference in the flexibility between types I and III collagen fibrils. This finding reveals potential physiological roles of type III collagen in regulating the mechanical properties of collagen fibrils and may enable the design of future collagen-like materials with tunable mechanical properties.