Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 16, Pages -Publisher
MDPI
DOI: 10.3390/ijms22169025
Keywords
calmodulin; calcium-binding protein; polyglutamine tract; polyglutamine disorders; Huntington's disease; molecular dynamics
Funding
- project: Entrepreneurship for innovation through doctoral and postdoctoral research [POCU/380/6/13/123886]
- European Social Fund, through the Operational Program for Human Capital 2014-2020
- CNCS/CCCDI UEFISCDI, within PNCDI III [PNIII-P2-2.1-PED-2016-0983]
- World Federation of Scientists, CERN, Geneva
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The study reveals that m-HTT proteins and CaM interact in the cerebral cortex, affecting intracellular calcium levels. The 9P(EM) model has the most significant impact on the structure and fluctuation rate of CaM, with lower interaction energies compared to the 45Qs-HTT mutant model.
Mutant huntingtin (m-HTT) proteins and calmodulin (CaM) co-localize in the cerebral cortex with significant effects on the intracellular calcium levels by altering the specific calcium-mediated signals. Furthermore, the mutant huntingtin proteins show great affinity for CaM that can lead to a further stabilization of the mutant huntingtin aggregates. In this context, the present study focuses on describing the interactions between CaM and two huntingtin mutants from a biophysical point of view, by using classical Molecular Dynamics techniques. The huntingtin models consist of a wild-type structure, one mutant with 45 glutamine residues and the second mutant with nine additional key-point mutations from glutamine residues into proline residues (9P(EM) model). Our docking scores and binding free energy calculations show higher binding affinities of all HTT models for the C-lobe end of the CaM protein. In terms of dynamic evolution, the 9P(EM) model triggered great structural changes into the CaM protein's structure and shows the highest fluctuation rates due to its structural transitions at the helical level from alpha-helices to turns and random coils. Moreover, our proposed 9P(EM) model suggests much lower interaction energies when compared to the 45Qs-HTT mutant model, this finding being in good agreement with the 9P(EM)'s antagonistic effect hypothesis on highly toxic protein-protein interactions.
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