Solvent-Dependent Mechanical Response of De Novo Helix Repeat Proteins

Proteins perform diverse functions in biological systems, including catalysis, signaling, transport, and various mechanical roles. The growing efforts to integrate proteins' unique functionalities into synthetic environments have stimulated research on protein behaviors in non-native, synthetic environments, such as in organic solvents or plastics. This study bridges the understanding of protein mechanics in nature with their application in synthetic environments. We used all-atom molecular dynamics simulations to study the unfolding of de novo helix repeat proteins in organic solvents at different hydration ratios under mechanical force. The results show that proteins in organic solvents require higher unfolding forces than in aqueous media and display distinct unfolding pathways. Detailed analysis revealed that sufficient replenishment of hydrogen bonding between protein and water favors helix unraveling, whereas the reduced hydrophobic effect in organic solvents encourages the breakdown of tertiary structure. These findings contribute critical insights into the rational design of proteins as unique mechanosensitive elements in synthetic materials, highlighting the importance of considering environmental context when repurposing proteins for such environments.