Molecular Mechanism of Transition from Catch-Bond to Slip-Bond in Fibrin

TL;DR

This study uncovers the molecular mechanism behind the transition from catch-bond to slip-bond behavior in fibrin's A:a knob-hole bonds, revealing a tension-dependent switch involving flap dissociation and interface remodeling that influences clot stability.

Contribution

It introduces a molecular model explaining the catch-to-slip bond transition in fibrin, highlighting the role of the movable flap as a tension-sensitive switch and developing a fluctuating bottleneck theory.

Findings

Flap dissociation triggers bond strengthening under tension.

The model quantifies interface stiffness and transition distances.

Strengthening bonds may enhance clot formation under shear.

Abstract

The lifetimes of non-covalent A:a knob-hole bonds in fibrin probed with the optical trap-based force-clamp first increases ("catch bonds") and then decreases ("slip bonds") with increasing tensile force. Molecular modeling of "catch-to-slip" transition using the atomic structure of the A:a complex reveals that the movable flap serves as tension-dependent molecular switch. Flap dissociation from the regulatory B-domain in $\gamma$-nodule and translocation from the periphery to knob `A' triggers the hole `a' closure and interface remodeling, which results in the increased binding affinity and prolonged bond lifetimes. Fluctuating bottleneck theory is developed to understand the "catch-to-slip" transition in terms of the interface stiffness $\kappa =$ 15.7 pN nm $^{-1}$, interface size fluctuations 0.7-2.7 nm, knob `A' escape rate constant $k_0 =$ 0.11 nm$^2$ s$^{-1}$, and transition distance for dissociation $\sigma_y =$ 0.25 nm. Strengthening of the A:a knob-hole bonds under small tension might favor formation and reinforcement of nascent fibrin clots under hydrodynamic shear.