Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics

Abstract

Native transthyretin (TTR) homotetramer dissociation is the first step of the fibrils formation process in amyloid disease. A large number of specific point mutations that destabilize TTR quaternary structure have shown pro-Amyloidogenic effects. Besides, several compounds have been proposed as drugs in the therapy of TTR amyloidosis due to their TTR tetramer binding affinities, and therefore, contribution to its integrity. In the present paper we have explored key positions sustaining TTR tetramer dynamical stability. We have identified positions whose mutations alter the most the TTR tetramer equilibrium dynamics based on normal mode analysis and their response to local perturbations. We have found that these positions are mostly localized at β-strands E and F and EF-loop. The monomer-monomer interface is pointed out as one of the most vulnerable regions to mutations that lead to significant changes in the TTR-Tetramer equilibrium dynamics and, therefore, induces TTR amyloidosis. Besides, we have found that mutations on residues localized at the dimer-dimer interface and/or at the T4 hormone binding site destabilize the tetramer more than the average. Finally, we were able to compare several compounds according to their effect on vibrations associated to the ligand binding. Our ligand comparison is discussed and analyzed in terms of parameters and measurements associated to TTR-ligand binding affinities and the stabilization of its native state.