Breakout character of islet amyloid polypeptide hydrophobic mutations at the onset of type-2 diabetes

TL;DR

This study investigates how specific hydrophobic mutations in the islet amyloid polypeptide influence aggregation propensity at the onset of type-2 diabetes, using a simplified model to quantify their effects.

Contribution

It introduces a minimalist one-bead hydrophobic-polar model to accurately predict aggregation propensities based on sequence mutations.

Findings

Hydrophobic mutations significantly affect aggregation free-energy barriers.

The model successfully correlates mutations with aggregation tendencies.

Hydrophobic hot spots are key targets for peptide stabilization.

Abstract

Toxic fibrillar aggregates of Islet Amyloid PolyPeptide (IAPP) appear as the physical outcome of a peptidic phase-transition signaling the onset of type-2 diabetes mellitus in different mammalian species. In particular, experimentally verified mutations on the amyloidogenic segment 20-29 in humans, cats and rats are highly correlated with the molecular aggregation propensities. Through a microcanonical analysis of the aggregation of IAPP_{20-29} isoforms, we show that a minimalist one-bead hydrophobic-polar continuum model for protein interactions properly quantifies those propensities from free-energy barriers. Our results highlight the central role of sequence-dependent hydrophobic mutations on hot spots for stabilization, and so for the engineering, of such biological peptides.