Fibrinogen-Amyloid beta peptide interactions in Alzheimer’s disease

Recent studies have suggested that fibrinogen, interacts with the β-Amyloid (Aβ) protein, contributing to formation of abnormal clots in cerebral vessels of patients with Alzheimer‟s disease (AD). Structure of fibrinogen includes a central E domain (FragE) with flanking coiled coil wings terminating to C-terminal D modules (FragD). Each FragD is consisted of globular protein domains, namely A, B and G. It can be converted to insoluble fibrin, a process which is essential for blood coagulation. Fibrin clot formation is resulted from the interaction between „knobs‟ on FragE with the „holes‟ on FragD. A milestone in study of AD is the discovery of Aβ irreversible interaction with fibrinogen and induction of abnormal clot formation. We applied the molecular modeling methods to address the question what are the essential residues in this pathogenic interaction. We designed and performed a method to verify the necessity of conformational changes in the fibrinogen structure. Studies showed that the fibrinogen must undergo conformation change to make the B-dog accessible for Aβ binding. Our methods for comprehensive deduction of critical amino acids of Aβ in Aβ-fibrinogen interactions, led to discovering that the key residues align on the α-helices of the Amyloid-β, on the inner side of the L-shaped Aβ structure. Calculation of interactions showed that the hydrogen bond and hydrophobic contacts are the main types of interaction between fibrinogen and Aβ peptide. These finding can help us for future drug design studies to inhibit the Aβ-fibrinogen interaction, as a strategy for AD therapy.

Keywords:

Protein-protein interaction , Alzheimer‟s disease (AD) , Amyloid-β , Fibrinogen , Drug Design , Clot Lysis