Folding and misfolding of Huntingtin protein from a coevolutionary perspective

Abstract

Huntington’s disease is an inherited neurodegenerative disorder caused by the overduplication of CAG repeats in the Huntingtin gene. There exists strong correlation between the extended polyglutamines (polyQ) within exon-1 of Huntingtin protein (Htt) and age onset of Huntington’s disease (HD). However, the underlying molecular mechanism is still poorly understood. We have applied extensive molecular dynamics simulations to study the folding of the pathogenic Htt-exon-1 across different polyQ-lengths and different species. By examining the radii of gyration, secondary structures and residue-residue interactions of Htt-exon-1 with these various sequences, we found that the polyP segments “chaperone” the rest of the HttEx1 by forming ad hoc polyP binding grooves. Such a process elongates the otherwise poorly solvated polyQ domain, while modulating its secondary structure propensity from β-strands to α-helices. This chaperoning effect is achieved mostly through transient hydrogen bond interactions between polyP and the rest of HttEx1, resulting in a striking golden ratio of ∼2:1 between the chain lengths of polyQ and polyP.