Yalinca, Havva Gehin, Charlotte Julie Caroline Oleinikovas, Vladimiras Lashuel, Hilal A. Gervasio, Francesco Luigi Pastore, Annalisa Presentation_1_The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus.pdf <p>Huntington disease is a neurodegenerative disease characterized by a polymorphic tract of polyglutamine repeats in exon 1 of the huntingtin protein, which is thought to be responsible for protein aggregation and neuronal death. The polyglutamine tract is preceded by a 17-residue sequence that is intrinsically disordered. This region is subject to phosphorylation, acetylation and other post-translational modifications in vivo, which modulate its secondary structure, aggregation and, subcellular localization. We used Molecular Dynamics simulations with a novel Hamiltonian-replica-exchange-based enhanced sampling method, SWISH, and an optimal combination of water and protein force fields to study the effects of phosphorylation and acetylation as well as cross-talk between these modifications on the huntingtin N-terminus. The simulations, validated by circular dichroism, were used to formulate a mechanism by which the modifications influence helical conformations. Our findings have implications for understanding the structural basis underlying the effect of PTMs in the aggregation and cellular properties of huntingtin.</p> Huntington's disease;misfolding disease;molecular dynamics;peptide folding;phosphorylation;post-translational modifications;enhanced sampling 2019-10-01
    https://frontiersin.figshare.com/articles/presentation/Presentation_1_The_Role_of_Post-translational_Modifications_on_the_Energy_Landscape_of_Huntingtin_N-Terminus_pdf/9922796
10.3389/fmolb.2019.00095.s001