Molecular Mechanisms of Transition from Catch to Slip Bonds in Fibrin

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 γ-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 κ = 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 σ 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. arXiv:1709.05727v1 [physics.bio-ph] 17 Sep 2017 unusual strengthening with the increasing pulling force applied to disrupt the bond, but the nature of this finding remained unclear. Such counterintuitive behavior has been described in the literature for a number of receptor-ligand pairs as the "catch" bond 9, 10 in contrast to the commonly known "slip" bond that dissociates faster with the increasing force. Interestingly, a non-covalent bond can behave as a catch bond at low forces (typically <30-40 pN) and as a slip bond at higher forces, thus displaying the dual "catch-slip" character. Several receptor-ligand complexes showing the catch-slip transition have been characterized including coupled cell adhesion molecules and glycoprotein ligand-1, 10 E-cadherin dimer, 11 integrin α5β 1 and fibronectin, 12 bacterial adhesin FimH, 13, 14 von Willebrand factor and receptor GP1b, 15, 16 actomyosin, 17 microtubulekinetochore, 18 and microtubule-dynein 19, 20 complexes. The catch-slip phenomenon was studied experimentally 14, 15, 21-24 and computationally. 14, 25-30 Theoretical models have been purposed including the two-state model, 31, 32 two-pathway model, 33 sliding-rebinding model, 34 hydrogen bond network model, 35 and other models. 36, 37 Yet, the atomic-level structural basis underlying the catch-slip transition in receptor-ligand complexes has eluded detailed characterization 9 .Here, we combined the single-molecule forced unbinding experiments in vitro and in silico using nanomechanical measurements and Molecular Dynamics (MD) simulations to resolve the structural mechanism underlying the dual catch-slip response of fibrin polymers to tension. We show that the strength of A:a knob-hole bonds first increases with tensile force up to f ≈ 30-35 pN (catch bond) and then decreases with force at f > 35 pN (slip bonds). Forced dissociation assays in silico revealed dynamic remodeling of the A:a association interface, which results in a manifold of bound states with tension-de...