Spontaneous formation of polyglutamine nanotubes with molecular dynamics simulations.

Expansion of polyglutamine (polyQ) beyond the pathogenic threshold (35-40 Gln) is associated with several neurodegenerative diseases including Huntington's disease, several forms of spinocerebellar ataxias and spinobulbar muscular atrophy. To determine the structure of polyglutamine aggregates we perform replica-exchange molecular dynamics simulations coupled with the optimized potential for effective peptide forcefield. Using a range of temperatures from 250 to 700 K, we study the aggregation kinetics of the polyglutamine monomer and dimer with chain lengths from 30 to 50 residues. All monomers show a similar structural change at the same temperature from alpha-helical structure to random coil, without indication of any significant beta-strand. For dimers, by contrast, starting from random structures, we observe spontaneous formation of antiparallel beta-sheets and triangular and circular beta-helical structures for polyglutamine with 40 residues in a 400 ns 50 temperature replica-exchange molecular dynamics simulation (total integrated time 20 micros). This approximately 32 A diameter structure reorganizes further into a tight antiparallel double-stranded approximately 22 A nanotube with 22 residues per turn close to Perutz' model for amyloid fibers as water-filled nanotubes. This diversity of structures suggests the existence of polymorphism for polyglutamine with possibly different pathways leading to the formation of toxic oligomers and to fibrils.