Atomistic MD Simulations Reveal the Protective Role of Cholesterol in the Membrane Disruptive Effects of Dimeric Beta-Amyloid in Neuronal Membrane Mimics

Abstract

Islet amyloid polypeptide (IAPP) is an intrinsically disordered protein involved in regulating glucose metabolism and gastric emptying. It plays a crucial role in beta cell failure in diabetes type II, where it accumulates in the form of amyloid fibers. Human IAPP (hIAPP) is arguably the most amyloidogenic naturally occurring peptide known so far. Recent work by Raleigh and coworkers shows that a single-point mutation (I26P) converts it into an effective in vitro amyloid inhibitor 1,2. The I26P mutation has been proposed to inhibit fibril formation by affecting the ability of the disordered C terminal tail to rearrange into the amyloid fibril structure, while maintaining intact the conformational properties of the N-terminal region, putatively responsible for the formation of aggregate intermediates 1,2. Though such mechanism has been proposed, the conformational and dynamical properties of the I26P monomer have not been experimentally determined yet. We use tryptophan triplet quenching by cystine to measure the rate of contact formation between the two ends of the I26P peptide. This technique has previously revealed conformational differences between rIAPP and hIAPP 3. It allows detecting both changes in the equilibrium end-to-end distance distribution and in the diffusional dynamics of the end-to-end distance caused by fast reconfigurations of backbone dihedral angles. We compare results for I26P, hIAPP, rIAPP, and model worm like chain peptides of same length. We discuss the effect of proline substitutions on the conformation and dynamics of these intrinsically disordered proteins and their possible effect on amyloid aggregation.