Molecular Mechanisms, Thermodynamics, and Dissociation Kinetics of Knob-Hole Interactions in Fibrin*□S

Background: Knob-hole interactions underlie formation and properties of fibrin polymer, the scaffold of blood clots and thrombi. Results: The structural mechanisms, dissociation kinetics, and thermodynamic parameters of the A:a and B:b knob-hole interactions have been determined. Conclusion: The knob-hole bonds are inherently variable and sensitive to pH and temperature. Significance: The emerging molecular picture offers mechanistic insights into fibrin polymerization. Polymerization of fibrin, the primary structural protein of blood clots and thrombi, occurs through binding of knobs ‘A’ and ‘B ’ in the central nodule of fibrin monomer to complemen-tary holes ‘a ’ and ‘b ’ in the - and -nodules, respectively, of anothermonomer.We characterized the A:a and B:b knob-hole interactions under varying solution conditions using molecular dynamics simulations of the structural models of fibrin(ogen) fragment D complexed with synthetic peptides GPRP (knob ‘A’ mimetic) andGHRP (knob ‘B’mimetic). The strength of A:a an