Contrasting Local and Macroscopic Effects of Collagen Hydroxylation

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.

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“…Proline (PRO) hydroxylation degree (HD) is an important factor affecting collagen properties, including mechanical behavior [31] and thermal stability [32]. The larger number of the hydroxyproline (HYP) residues, the higher the denaturation temperature.…”

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“…[41][42][43][44] As expected, the structural consequences have an impact on the crucial properties of the considered biopolymer. According to Varma et al, 45 the number of hydroxyl groups attached to proline (PRO) in collagen slightly affects the mechanical properties of collagen. Furthermore, the significant effect of HYP on collagen stability results in increasing the denaturation temperature with the increasing HYP/PRO ratio.…”