Multi-scale molecular modelling and large-scale computer simulations

Aggregation of transthyretin (TTR) is associated with devastating amyloid diseases. Amyloidosis begins with the dissociation of the native homotetramer (a dimer of dimers) to form a monomeric intermediate that assembles into pathogenic aggregates. The mechanism by which TTR dissociates and reassembles remains poorly characterized due to experimental limitations. The aim of this project is to gain structural insights into the association pathway of the native and a destabilized variant, V30M, of TTR. In particular, we will perform enhanced sampling methods and classical molecular dynamics simulations to model the self-assembly process of these proteins to identify the potential oligomeric species associated with amyloidosis.