Conformations of the Huntingtin N-term in aqueous solution from atomistic simulations

The first 17 amino acids of Huntingtin protein (N17) play a crucial role in the protein’s aggregation. Here we predict its free energy landscape in aqueous solution by using bias exchange metadynamics. All our findings are consistent with experimental data. N17 populates four main kinetic basins, which interconvert on the microsecond time-scale. The most populated basin (about 75%) is a random coil, with an extended flat exposed hydrophobic surface. This might create a hydrophobic seed promoting Huntingtin aggregation. The other main populated basins contain helical conformations, which could facilitate N17 binding on its cellular targets.

► The N17 region of Huntingtin plays a crucial role for the aggregation of the protein in Huntington disease.
► Simulations provide full-atom characterization of N17’s conformational ensembles in explicit solvent.
► All our results are in agreement with the available experimental data.
► The knowledge of the structural determinants of N17 may help elucidate how this region modulates Huntingtin aggregation.