Abstract
Collagens are the most abundant structural proteins in the extracellular matrix of animals and play crucial roles in maintaining the structural integrity and mechanical properties of tissues and organs while mediating important biological processes. Fibrillar collagens have a unique triple helix structure with a characteristic repeating sequence of (Gly-X-Y)(n). Variations within the repetitive sequence can cause misfolding of the triple helix, resulting in heritable connective tissue disorders. The most common variations are single-point missense mutations that lead to the substitution of a glycine residue with a bulkier amino acid (Gly → X). In this review, we will first discuss the importance of collagen's triple helix structure and how single Gly substitutions can impact its folding, structure, secretion, assembly into higher-order structures, and biological functions. We will review the role of "designer collagens," i.e., synthetic collagen-mimetic peptides and recombinant bacterial collagen as model systems to include Gly → X substitutions observed in collagen disorders and investigate their impact on structure and function utilizing in vitro studies. Lastly, we will explore how computational modeling of collagen peptides, especially molecular and steered molecular dynamics, has been instrumental in probing the effects of Gly substitutions on structure, receptor binding, and mechanical stability across multiple length scales.