Conformational Characterization and Classification of Intrinsically Disordered Amyloid-beta( 1-42) Through Molecular Dynamics Simulations

Abstract

Intrinsically disordered proteins (IDPs) are a group of proteins that lack the ability to fold into a well-defined 3D structure. These proteins comprise a significant fraction of eukaryotic proteomes. The free energy landscapes of these proteins are assumed to have many competing low-energy states leading to an absence of a single tertiary structure. Characterizing their conformational spaces can be difficult by using standard experimental and computational techniques. Amyloid-β (Aβ) peptide, a prototypic IDP, aggregates into fibrils implicated in the pathogenesis of Alzheimer’s disease (AD). This thesis focuses on defining conformational states of the Aβ42 monomer using molecular dynamics (MD) simulations to better understand the conformational changes of IDPs

The beginning of amyloid aggregation includes a conformational transition from α- to β-dominated form of the Aβ42 monomer. We conducted simulations starting from one helical structure and one monomeric unit of the β-sheet fibril in aqueous solution. We assumed that simulations from both directions would converge to an intermediate structure existing during the α-to-β transition. This intermediate structure is, in fact, a collection of conformational states sampled from this IDP.

Previous nuclear magnetic resonance and cryo-EM studies provided the molecular description for Aβ fibre polymorphism. MD simulations were performed in aqueous solution starting from monomeric systems based on these atomic structures. By merging structural ensembles into the same trajectory, the conformational space of the Aβ42 monomer was summarized using principal component analysis. This ensemble suggests possible paths between configurational states. I classified these heterogeneous conformers without a single fixed structure using alternative and novel approaches. Combining these, I have re-defined key structural elements of the monomeric form of the Aβ42 tertiary structure.

MD simulations of the Aβ42 monomer in ethanol-water cosolvents were implemented successively as a function of ethanol composition, mimicking the change of environment polarity. I demonstrated that the monomeric form reverts to an extended α-helix in a low polarity environment. It is concluded that the α-to-β transition could be reversible by altering the solvent polarity. Observations and analyses on Aβ42 interacting with ethanol suggest similar behaviours of the peptide as when it binds with lipid membranes. Significantly, the central methodology of this thesis could be applicable for characterizing and categorizing structures of other IDPs.