Understanding the disrupting mechanism of the Tau aggregation motif “306VQIVYK311” by phenylthiazolyl-hydrazides inhibitors

Elena Moreno-Castillo, Yoanna M. Álvarez-Ginarte, Mario E. Valdés-Tresanco, Luis A. Montero-Cabrera, Ernesto Moreno, Pedro A. Valiente

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Alzheimer's disease is a progressive neurodegenerative disorder characterized by the abnormal processing of the Tau and the amyloid precursor proteins. The unusual aggregation of Tau is based on the formation of intermolecular β-sheets through two motifs: 275VQIINK280 and 306VQIVYK311. Phenylthiazolyl-hydrazides (PTHs) are capable of inhibiting/disassembling Tau aggregates. However, the disaggregation mechanism of Tau oligomers by PTHs is still unknown. In this work, we studied the disruption of the oligomeric form of the Tau motif 306VQIVYK311 by PTHs through molecular docking, molecular dynamics, and free energy calculations. We predicted hydrophobic interactions as the major driving forces for the stabilization of Tau oligomer, with V306 and I308 being the major contributors. Nonpolar component of the binding free energy is essential to stabilize Tau-PTH complexes. PTHs disrupted mainly the van der Waals interactions between the monomers, leading to oligomer destabilization. Destabilization of full Tau filament by PTHs and emodin was not observed in the sampled 20 ns; however, in all cases, the nonpolar component of the binding free energy is essential for the formation of Tau filament-PTH and Tau filament-emodin. These results provide useful clues for the design of more effective Tau-aggregation inhibitors.

Original languageEnglish
Article numbere2848
JournalJournal of Molecular Recognition
Volume33
Issue number9
DOIs
StateAccepted/In press - 1 Jan 2020

Keywords

  • LIE
  • MM-GBSA
  • molecular docking
  • molecular dynamics
  • phenylthiazolyl-hydrazides
  • Tau protein

Product types of Minciencias

  • C article - Q4

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