Heterogeneity in conformational state space enhances the force-tolerance of mechanosensory proteins

Abstract β-strands in proteins undergo anti-cross correlated crankshaft-type motions and adapt to the input mechanical cues. However, a direct study to reveal the molecular relation of force-adaptability with crankshaft motions of β-strands is long-awaited. To elucidate, here we explore the differences in mechanical tolerance of a gating-spring protein in hearing, cadherin-23, with genotypic and phenotypic variations on a single residue. Though the variants possess comparable topology, differ in contact-orders. Higher contact-order induces higher crankshaft. We identified that the variants with higher crankshaft exhibit larger heterogeneity in the conformational state space and thus, higher force-tolerance. However, protein-variants with lower contact-orders possess higher folding-cooperativity and faster intrinsic-folding, though their folding-energy landscape is most prone to distortion under tension. Overall, our study provides a unique relation between the transition-cooperativity amongst the sparsely populated conformational states and the force-adaptations by β-rich proteins. The use of phenotype and genotype variants also help us to deduce the mechanical fingerprinting of healthy spring and malicious spring.