Probing the role of V30M mutation in human transthyretin aggregation using molecular simulations

Transthyretin (TTR), also known as prealbumin, is a highly conserved protein found in several vertebrate species. Dissociation of TTR tetramer followed by aggregation and misfolding of the monomers causes genesis of insoluble amyloid fibrils, which might systematically lead to peripheral and/or autonomic neuropathy and other systemic manifestations. Structural insights into the conformational landscape of TTR monomers upon mutation are useful for understanding amyloid aggregation. In this study, we used all-atom molecular dynamics (MD) simulations to investigate the role of V30M mutation on the structure of TTR monomer. The MD simulations of the wild-type and V30M TTR monomeric showed that the V30M mutation leads to dissociation of one of the edge strands, strand C, from the core of the monomer and forms an ensemble of partially unfolded conformations. These changes can be linked to disruption in the inter-strand hydrogen bonding and the secondary structure of the monomeric state. Moreover, non-covalent interactions in the E-F loop region, which is important for aggregation propensity of TTR, are also perturbed. Overall, the MD simulations provide comparative structural insights into the dynamics of wild-type and V30M TTR monomers.