Addressing Mysteries of the Collagen Triple Helix with All-atom Molecular Dynamics Simulation and Experiments

Synopsis

Collagen is the most ubiquitous protein in eukaryotes, comprising ~50% of total protein mass in tendons. Collagen "folds" into a rope-like trimeric structure formed by a Gly-Xaa-Yaa-repeat sequence motif. These collagen triple helices fibrillize to form structures, such as bone, which serve as the principal determinant of tissue stiffness. Several aspects of the collagen triple helix remain unresolved, including how the protein sequence determines helical pitch, mechanical properties, and fiber formation. This is in part due to the intrinsic challenges of studying the triple helix due to this characteristic residue repeat motif, the non-covalently trimerized triple helical structure, and the tendency for collagens to aggregate.

We have used collagen-mimetic peptides that feature the Gly-Xaa-Yaa repeat and fold into a triple helix and data from chemical physics experiments to evaluate the capacity for physics-based Molecular Dynamics (MD) simulations to accurately model the structure, mechanics, and dynamics of collagen. Using the most accurate MD simulation methods available, we have investigated key features of the collagen triple helix, including mechanics of >300-nm-long natural collagen triple helices, triple helix dimerization, and the variations in the collagen helical pitch. This work will serve as the basis for future investigations into the molecular determinants of collagen association, fiber structure and mechanics, and collagen-protein interactions through a combination of MD simulation, experiment, and other computational approaches.