Specific Key-Point Mutations along the Helical Conformation of Huntingtin-Exon 1 Protein Might Have an Antagonistic Effect on the Toxic Helical Content’s Formation

Abstract

The polyglutamine tract length represents a key regulator for the Huntington's disease toxicity level and its aggregation rates, often being related to helical structural conformations. In this study, we performed all-atom MD simulations on mutant Huntingtin-Exon1 protein with additional mutation spots, aiming to observe the corresponding structural and dynamical changes at the level of the helix. The simulated structures consist of three sets of Q residue mutations into P residues (4P, 7P, and 9P), with each set including different spots of mutations: random along the mutant sequence (R models), at the edges of the helix (E models), as well as at the edges and in the middle of the helix (EM models). At the helical level, our results predict less compactness profiles for a higher number of P mutations (7P and 9P models) with particular mutation spots at the edges and at the edges-middle of the helix. Moreover, the C-alpha atom distances decreased for 7P and 9P models in comparison to 4P models, and the RMSF values show the highest fluctuation rates for 9P models with point mutations at the edges and in the middle of the helix. The secondary structure analysis suggests greater structural transitions from α-helices to bends, turns, and random coils for 7P and 9P models, particularly for point mutations considered at the edges and in the middle of the helical content. The obtained results support our hypothesis that specific key-point mutations along the helical conformation might have an antagonistic effect on the toxic helical content's formation.