Functions of prolyl hydroxylation in elastin

Elastin is a key protein responsible for elasticity, resilience, and deformability of tissues. Elastin is subject to an understudied posttranslational modification, prolyl hydroxylation, where a hydroxyl group replaces a hydrogen atom at C-γ in proline residues during assembly. Recent experimental studies suggest elastin-like peptides with hydroxyproline modifications are more resistant to enzymatic digestion and subject to abnormal assembly. We hypothesize that hydroxylation modulates protein-solvent interactions, thereby altering elastin behavior. To test our hypothesis, we build representative models with and without prolyl hydroxylation and perform extensive molecular dynamics simulations. Our findings suggest that hydroxyproline increases hydrogen bonding with water by an average of 135% compared to proline, which reduces the local configurational space, thereby negatively impacting elastin's global dynamics, essential for its biological functions. This modification may potentially protect the molecule from targeted degradation and modulate canonical hierarchical assembly. In addition, our study provides design insights for engineered elastin-based materials through fine-tuning of hydroxyproline content.