Electrostatic and hydrophobic interactions of lipid-associated alpha synuclein: The role of a water-limited interfaces in amyloid fibrillation

Abstract

Human alpha-synuclein (alpha Syn) is an intrinsically disordered protein (IDP) whose biological and pathological functions in brain neuronal cells have not yet been fully elucidated. alpha Syn intrinsically participates in aiding neurotransmitter trafficking through aSyn the association with lipid membranes. However, lipid-associated states of alpha Syn also induce amyloid self-assembly that is linked to the pathogenesis of various synucleinopathies. These contradicting actions arise from the limited water content near lipid-water interfaces that controls alpha Syn electrostatic and hydrophobic interactions. Thus, understanding the molecular interactions between alpha Syn and lipid membranes in the presence of water molecules is critical in elucidating the pivotal role of lipid-associated alpha Syn in amyloid self-assembly. In this review, we describe how the membrane interface controls electrostatic and hydrophobic interactions of lipid-associated alpha Syn. Moreover, membrane amyloid self-assembly of alpha Syn will be further discussed with regards to the structural dynamics of lipid-associated alpha Syn and water molecules near the interface.