Obtention of accurate Abeta-Zn(II) ensembles from molecular modelling and Bayesian/maximum entropy reweighing.

Abstract

Amyloid fibrils are stable forms of misfolded proteins associated with numerous neurodegenerative diseases. Among these, Alzheimer's disease may be the most prevalent, with over 55 million dementia cases reported by the World Health Organisation in 2021. The molecular origin of Alzheimer's is linked to amyloid fibril formation by misfolded Aβ-peptide (Aβ). These fibrils form aggregates that are stabilised by the presence of Zn(II) cations. Many possible Aβ-Zn(II) structures have been proposed experimentally (see Figure 1) where Zn(II) adopts different coordinations. To obtain a representative and accurate ensemble of Aβ-Zn(II) systems is challenging as standard Zn(II) models employed by classical force fields, i.e., nonbonded models, tend to fail. These models heavily favour octahedral coordination although it has been reported that tetrahedral coordination is favoured in the protein environment. In this work, we will employ bonded models to accurately capture Aβ-Zn(II) coordination and extract precise conformational dynamics of the systems. Additionally, we use Bayesian/Maximum Entropy reweighing to obtain a more accurate ensemble description of these systems.