Structural insight to mutated Y116S transthyretin by molecular dynamics simulation

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Familial amyloidotic polyneuropathy (FAP) is linked to transthyretin (TTR) protein mutations.
• The Tyr116Ser (Y116S) TTR variant is a significant amyloidogenic mutation causing FAP.

Purpose of the Study:

• To investigate the structural dynamics of wild-type and Y116S mutant TTR monomers.
• To gain molecular insights into structural transitions related to amyloid formation.

Main Methods:

• Molecular dynamic simulation at 310 K was performed on wild-type and Y116S mutant TTR monomers.
• Analysis focused on structural transitions within the protein's inner and outer strands.

Main Results:

• The Y116S mutation disrupts the secondary structure and hydrogen bonding in the protein's inner DAGH-sheet.
• Specific residues (T106, A108, L110, S117, T119) involved in thyroxine binding are affected.
• The unfolding of the mutant structure suggests increased protein instability.

Conclusions:

• The Y116S mutation induces structural instability in TTR monomers.
• This instability is a potential mechanism driving amyloidogenesis in FAP.