Sequence-dependent mechanics of collagen proteins reflect their structural and functional organization

Collagens are the predominant proteins in vertebrates, forming diverse hierarchical structures to support cells and form connective tissues. Despite their mechanical importance, surprisingly little is established about the molecular encoding of mechanics. Here, we combine position-dependent flexibility analysis with single-molecule imaging by atomic force microscopy (AFM), and find that collagens exhibit variable flexibility along their backbones. We identify a region of high bending flexibility around the matrix metalloprotease (MMP) binding site in a fibril-forming collagen. This result represents the first demonstration of a unique mechanical signature of the MMP site, key for remodeling of the extracellular matrix during development and disease. By comparing collagens with continuous and discontinuous triple-helix-forming sequences, we find that the type of helix interruption correlates with local flexibility, providing a step towards a much-needed map between sequence, structure, and mechanics in these large proteins. Our results inform our understanding of collagen’s ability to adopt compact conformations during cellular secretion and suggest a physical mechanism by which higher-order structure may be regulated by the distinct molecular properties of different collagens.