Abstract

Familial Amyloidal Cardiomyopathy (FAC) is a genetic disease where amyloid fibrils aggregate into plaques around the heart. The disease is caused by the dissociation and aggregation of mutant forms of the transport protein transthyretin (TTR). The TTR mutant studied here had Valine-122 substituted with an Isoleucine. This mutation was chosen due to its presence in 3% of the African American community. AG10,an experimental treatment, and its derivatives work by stabilizing TTR and preventing disassociation and subsequent plaque formation. Molecular Dynamics (MD) simulations were used to study how the AG10 derivative TKS-14 and other similar compounds bind to and stabilize TTR. Our hypothesis was to test the extent to which MD simulations could provide atomic scale insight into the binding of TKS-14 and its derivatives to TTR. These insights could potentially help researchers design new compounds that to stabilize TTR and treat FAC.  We analyzed H-bond formation between the ligands and TTR. MD simulation analyses showed that TKS-14 binds to TTR by forming H-bonds with Ser-117 residues in the inner TTR binding pocket and interacting with Lys-15 residues near the receptor’s surface. When the TKS-14 carboxylate functional group was modified, new hydrogen bond interactions between the ligand and TTR. These results lead to the conclusion that MD simulation analyses can lead to a better understanding of the intermolecular interactions experienced by TTR stabilizers.