Modelling pathological conformations in transthyretin amyloidosis

Abstract

The amyloidoses are a set of fatal disorders in which proteins aggregate and form fibrils that deposit in tissues throughout the body. Amyloid diseases are challenging to study as critical events in amyloid formation occur on timescales that span several orders of magnitude and involve heterogeneous, interconverting protein conformations. Consequently, there are few structural models of protein conformations associated with amyloid pathologies. The development of more effective technologies to diagnose and treat amyloid disease requires both a map of those conformations and an understanding of the molecular mechanisms that drive aggregation. Here, I present the results of simulations that benchmark the ilmm molecular dynamics simulation package against experimental data; simulations that model the conformational changes to transthyretin monomers that are predicted to occur prior to aggregation; simulations of host-guest pentapeptides used to construct conformational libraries that have applications in protein design; and simulations of a redesigned transthyretin variant that is engineered to have reduced conformational stability.