Abstract
Collagen is heavily hydroxylated. Experiments show that proline hydroxylation is important to triple helix (monomer) stability, fibril assembly, and interaction of fibrils with other molecules. Nevertheless, experiments also show that even without hydroxylation, type I collagen does assemble into its native D-banded fibrillar structure. This raises two questions. Firstly, even though hydroxylation removal marginally affects macroscopic structure, how does such an extensive chemical change, which is expected to substantially reduce hydrogen bonding capacity, affect local structure? Secondly, how does such a chemical perturbation, which is expected to substantially decrease electrostatic attraction between monomers, affect collagen’s mechanical properties? To address these issues, we conduct a benchmarked molecular dynamics study of rat type I fibrils in the presence and absence of hydroxylation. Our simulations reproduce the experimental observation that hydroxylation removal has a minimal effect on collagen’s D-band length. We also find that the gap-overlap ratio, monomer width and monomer length are minimally affected. Surprisingly, we find that de-hydroxylation also has a minor effect on the fibril’s Young’s modulus, and elastic stress build up is also accompanied by tightening of triple-helix windings. In terms of local structure, de-hydroxylation does result in a substantial drop (23%) in inter-monomer hydrogen bonding. However, at the same time, the local structures and inter-monomer hydrogen bonding networks of non-hydroxylated amino acids are also affected. It seems that it is this intrinsic plasticity in inter-monomer interactions that preclude fibrils from undergoing any large changes in macroscopic properties. Nevertheless, changes in local structure can be expected to directly impact collagen’s interaction with extra-cellular matrix proteins. In general, this study highlights a key challenge in tissue engineering and medicine related to mapping collagen chemistry to macroscopic properties but suggests a path forward to address it using molecular dynamics simulations.
Highlights
A wealth of information is available on the structure, assembly, and regulatory mechanisms of collagen in modulating tissue mechanics, cell interactions, and signaling [1,2,3]
We note first that the D-band length of hydroxylated collagen is 66.21 ± 0.03 nm, which is in close correspondence with estimates of ∼67 nm obtained from Atomic Force Microscopy, Transmission Electron Microscopy, and X-ray diffraction studies [1,2,3]
Collagen is the main protein in vertebrate tissue, and it is among the most hydroxylated of proteins
Summary
A wealth of information is available on the structure, assembly, and regulatory mechanisms of collagen in modulating tissue mechanics, cell interactions, and signaling [1,2,3]. In tissue engineering, it remains challenging to rationally design next-generation collagen scaffolds with improved mechanical strengths and capacities to interact with and influence cell signaling [4,5,6]. Addressing these issues from a fundamental standpoint requires a better understanding of how local chemical perturbations connect to their macroscopic responses. We examine this inter-scale relationship in the context of hydroxylation of Type I collagen
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