Interplay between Folding and Assembly of Fibril-Forming Polypeptides

Polypeptides can self-assemble into hierarchically organized fibrils consisting of a stack of individually folded polypeptides driven together by hydrophobic interaction. Using a coarse-grained model, we systematically studied this self-assembly as a function of temperature and hydrophobicity of the residues on the outside of the building block. We find the self-assembly can occur via two different pathways—a random aggregation-folding route and a templated-folding process—thus indicating a strong coupling between folding and assembly. The simulation results can explain experimental evidence that assembly through stacking of folded building blocks is rarely observed, at the experimental concentrations. The model thus provides a generic picture of hierarchical fibril formation.

Figure 1

Top: folded $\beta$-roll structure of a single polypeptide [alanine $(A)=\mathrm{\text{yellow}}$, isoleucine $(I)=\mathrm{\text{white}}$, glutamate $(E)=\mathrm{\text{red}}$, arginine $(R)=\mathrm{\text{blue}}$]. Bottom: equilibrium phase diagram in the $T^{*}\mathrm{\text{−}}{ϵ}_{A,w}$ plane, with transition temperatures for two polypeptides (squares) and the folding temperature of single polypeptide (circles). Typical snapshots of the isolated unfolded, aligned, and stacked phases are included.

Figure 2

Free energy landscape as a function of the silk-block center-to-center distance $R_{\mathrm{cc}}$, and the total number of hydrogen bonds $H_{\mathrm{tot}}$. Left column: ${ϵ}_{A,w}=0.6$, $T^{*}=0.4109$ (top) and 0.3907 (bottom). Right column: ${ϵ}_{A,w}=0.01$ at the temperature $T^{*}=0.402$ (top) and 0.387 (bottom). Solid circles denote saddle points.

Figure 3

Main: heat capacity versus temperature for two polypeptides at various concentrations with ${ϵ}_{A,w}=0.6$. Inset: the reciprocal transition temperature $T_c$ versus the logarithm of peptide concentration. In both plots the dashed line indicates the single polypeptide folding temperature.