Schematic representation of fibrin molecules bearing knobs and holes that bind each other in the course of fibrin polymerization. (A) A fibrin monomer is 45 nm long and consists of 3 parts, namely 2 D-regions and 1 E-region. The D-regions contain the distal portions of the coiled-coil and the C-terminal β- and γ-modules. The E-region contains the central N-terminal part of the molecule and the proximal portions of both sets of coiled-coils. The E-region has 2 pairs of binding sites named A- and B-knobs that are exposed after cleavage of FpA and FpB by thrombin. The D-regions have constitutively open a- and b-holes located in the γ- and β-modules, respectively. (B) The driving force of fibrin polymerization is the complementary binding of the A-knobs and a-holes and perhaps of the B-knobs and b-holes resulting in formation of a half-staggered 2-strand protofibril. The cartoon is based on the crystallographic data and represents approximately the relative positions and dimensions of the molecular parts. The A- and B-knobs are highly flexible and hence have not been visualized in the crystal structure to date. (C) Cartoons of the molecules used in this study (fibrinogen, fragment D, and 3 types of the fragment called N-terminal disulphide knot, NDSK). The gray and black circles represent fibrinopeptides A (FpA) and B (FpB), respectively.