Structural insight to mutated Y116S transthyretin by molecular dynamics simulation.

Familial amyloidotic polyneuropathy (FAP) is strictly associated with point mutations of transthyretin (TTR) protein. The Tyr116 -> Ser (Y116S) mutant TTR is an important amyloidogenic variant responsible for FAP. Structural dynamics of monomeric TTR and its mutant (Y116S) may give some clue relating to amyloid formation. In this study, molecular dynamic simulation at 310 K has been performed on wild-type and mutant (Y116S) TTR monomer, which can provide the molecular insight of structural transition in the inner and outer strand of the protein. Results show that mutation in the H-strand (Tyr116 -> Ser) leads to disruption of secondary structure and H-bonding pattern of some important parts of the inner DAGH-sheet of the protein. Especially, the residues T106, A108, L110 of G-strand, S117 and T119 of H-strand are affected, which are involved in the binding of thyroxin hormone. This unfolding of mutant structure during dynamics may cause instability in the protein and thus induce amyloidgenesis.