Insights into Stabilizing Forces in Amyloid Fibrils of Differing Sizes from Polarizable Molecular Dynamics Simulations

Abstract

Pathological aggregation of amyloid-forming proteins is a hallmark of a number of human diseases, including Alzheimer's, type 2 diabetes, Parkinson's, and more. Despite having very different primary amino acid sequences, these amyloid proteins form similar supramolecular, fibril structures that are highly resilient to physical and chemical denaturation. To better understand the structural stability of disease-related amyloids and to gain a greater understanding of factors that stabilize functional amyloid assemblies, insights into tertiary and quaternary interactions are needed. We performed molecular dynamics simulations on human tau, amyloid-β, and islet amyloid polypeptide fibrils to determine key physicochemical properties that give rise to their unique characteristics and fibril structures. These simulations are the first of their kind in employing a polarizable force field to explore properties of local electric fields on dipole properties and other electrostatic forces that contribute to amyloid stability. Across these different amyloid fibrils, we focused on how the underlying forces stabilize fibrils to elucidate the driving forces behind the protein aggregation. The polarizable model allows for an investigation of how side-chain dipole moments, properties of structured water molecules in the fibril core, and the local environment around salt bridges contribute to the formation of interfaces essential for fibril stability. By systematically studying three amyloidogenic proteins of various fibril sizes for key structural properties and stabilizing forces, we shed light on properties of amyloid structures related to both diseased and functional states at the atomistic level.