A computational study on pathogenic exon-1 Huntington fragment fiber structure and its nucleation

Huntington is a genetic disease linked with the expansion of the poly glutamine (polyQ) sequence in the Huntington (htt) protein. It is known that when the length of the polyQ block exceeds 36, the N-terminal exon-1 fragment of htt protein self assembles into fibrils in patients' brains. The aggregation mechanism of exon-1 into fibrils and the structural details of the fibril are still not fully understood. Two of the most plausible mechanisms remain to be the N-terminal flanking domain httNT α-helix driven aggregation and membrane mediated aggregation. The structure of the exon-1 fragment inside the fiber consists of an amphiphatic α helix from the httNT , a compact core made up of polyQ β-hairpins, and an extended proline rich domain (PRD). On the contrary, isolated httNT and short polyQ domains in solution display an intrinsically disordered character. Understanding the conformational transition of these domains from the disordered state, to the structure in the fiber remains an outstanding question. This thesis work is organized into three chapters. In chapter three, we investigate the chain length dependence of polyQ secondary structure by using molecular dynamics simulations. Our analysis show that α-helical structures favored by short molecules are replaced by mixed structures with α and β character as polyQ length increases. In chapter four, we study the structure of the polyQ block within the fiber to construct a model in agreement with the experimental findings. Our computational model indicates that only the correlated behavior of χ1 and χ3 dihedral angles leads to the bimodal χ1 distribution observed in experiments. Furthermore, the bimodal χ angle distribution is essential for the formation of the steric zipper motif and the extended side chain blocks connected via hydrogen bonds in the polyQ block. Finally, by applying this model to the exon-1 fragment we test the viability of the α helical httNT block within the fiber structure. In the fifth chapter, we analyze the interaction of the httNT block with a membrane and its influence on the polyQ block's conformation and aggregation. We observe that the httNT fragment adopts a fully extended α-helical structure inside the membrane, but unlike bulk water it does not self associate. This strong anchoring by httNT leads to an increased concentration of polyQ blocks on the membrane surface. Comparison of the β-sheet vs. sandwich models of polyQ seeds, suggests that the steric zipper motif is key for further nucleation.