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

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 ${\mathrm{IAPP}}_{20\text{−}29}$ 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 thus for the engineering, of such biological peptides.

Figure 1

The thermodynamic behavior of segments of amylin isoforms such as cIAPP in green (light gray), rIAPP in black (black), and hIAPP in red (dark gray) as a function of energy $\left(E\right)$ per residue $\varepsilon =E/N.$ Upper panel: caloric curve. Center panel: microcanonical specific heat. Lower panel: the Helmholtz free-energy barrier (error bars are smaller than the circles).

Figure 2

Caloric curves for $2\times {\text{hIAPP}}_{20\text{−}29}$ as a function of energy $\left(E\right)$ per residue $\varepsilon =E/N$ as an illustration of various error sources in microcanonical simulations. Upper panel: energy bin-size effects for $▵E=0.1$ in black (black), $▵E=0.2$ in green (dark gray), $▵E=0.5$ in orange (gray), and $▵E=1.0$ in light gray (light gray). Central panel: finite-volume effect as a function of the linear size of the container radius for $R=80$ in green (dark gray), $R=100$ in black (black), $R=120$ in orange (gray), and $R=150$ in light gray (light gray). Lower panel: kernel-sized effects in finite-difference derivatives for $dE=0.5$ in light gray (light gray), $dE=1.0$ in orange (gray), $dE=1.5$ in green (dark gray), and $dE=2.0$ in black (black).