Collagen is a major component of the extracellular matrix (ECM) and provides physical support for cells and organs. Collagen also interacts with a diverse array of binding partners and plays a central role in constructing and remodeling the ECM. To date, 29 types of collagen have been discovered, among which type I collagen, found in skin and tendons, is the most abundant. Type I collagen is a heterotrimer triple helix, consisting of two α1(I) chains and one α2(I) chain. The three chains have a characteristic one-residue stagger, which leads to three distinct strands and a designation as leading, middle, or trailing chains. The sequence of collagen contains a repeating glycine-X-Y motif, where inter-chain hydrogen bonding stabilizes the triple helix. Mutations in the collagen sequence often disrupt the triple helix structure and are associated with many collagenopathies. For example, Osteogenesis Imperfecta (OI), a genetic bone disorder, is often related to glycine to serine mutations in the collagen sequence. Owing to the current challenge to synthesize well-defined heterotrimers, experimental studies largely focus on characterizing the effect of mutations in homotrimer α1(I) collagen. To better investigate the effects of mutations on type I collagen in biology, I use molecular dynamics simulations to model type I collagen heterotrimers consisting of two α1(I) chains and one α2(I) chain. Because the location of the α2(I) chain in the type I collagen triple helix is currently unknown, three sets of simulations are performed, where the α2(I) chain is placed on one of the three strands. To understand how glycine to serine mutations affect interactions between collagen and integrin, an important protein involved in the regulation of T cells, my model collagen sequence consists of the integrin-binding site GFOGER, and 6 triplets N- and C-terminal to it. The first glycine on the integrin-binding site (GFOGER) is then mutated on one, two, or all three chains. I find that a mutation on the α2(I) chain results in a greater disruption of inter-chain hydrogen bonds, compared to a mutation on the α1(I) chain. Furthermore, the first mutation has the largest reduction in triple helix stability, and subsequent mutations on multiple chains do not necessarily have additive effects. This work characterizes the effect of glycine to serine mutations in heterotrimer type I collagen models and elucidates the structural and functional changes type I collagen undergoes in OI.

Effect of Gly to Ser mutations at the integrin-binding site on type I collagen

253rd National Meeting (2017)

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