Unveiling the Architecture of Human Fibrinogen: A Full-Length Structural Model

Abstract

Fibrinogen is a protein involved in the haemostasis process playing a central role by forming the fibrin clot. An understanding of protein structure is vital to determining biological function. Despite many studies on the fibrin polymerization process, its molecular mechanism remains elusive mainly due to the absence of a full-length three-dimensional model of human fibrinogen. Amino- and carboxyl-terminal regions of the three pairs of chains that form this molecule are missing in the crystallographic structure, being the carboxyl-terminal of the Aα chain the most affected with a section of more than 400 amino acids missing. To have a full structure of the fibrinogen molecule would allow the creation of a model of protofibril, shedding light into the fibrin formation process through computational techniques such as molecular dynamics simulations. Absent regions were explored using homology modelling and coarse-grained molecular dynamics simulations. Later on, the model was refined and stabilized with atomistic molecular dynamic simulations. In the present study, we obtained the first realistic full-length structure of fibrinogen, with features in accordance with previous results obtained by experimental techniques.