Computational protocol: The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

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Protocol publication

[…] The Protein Data Bank (PDB) crystal structure of bovine brain tubulin 1JFF was repaired via homology modeling by adding missing residues from 1TUB using MODELLER 9V6 . The repaired 1JFF dimer was solvated, neutralized and energy-minimized using the molecular dynamics simulator NAMD , developed by the Theoretical and Computational Biophysics Group in the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign. Using this dimer, MT A and B lattice structures were built with PYMOL 0.99rc6 using MT geometry described in Li et al. and Sept et al. . [...] To analyze the electrostatics of the systems, hydrogens were added, and protonation states set at pH 7 with PROPKA , via PDB2PQR , for both the tubulin dimer and MT lattice structures. The Poisson-Boltzmann equation was solved for the structures in given arrangement with the Adaptive Poisson-Boltzmann Solver (APBS) with less than 1 Å spacing. To investigate the effect of the zinc ions of the electrostatic profile of tubulin the Poisson-Boltzmann equation was solved for the tubulin dimer both with zinc ions, at the top six sites. Zinc ions were given a charge of +2e and radius of 1.10 Å. Charges on the key binding residues were modified to allow zinc binding, partially canceling the zinc charge following the cationic dummy atom approach (CaDA) –: Cysteine and histidine residues were used in their anionic form, and glutamic acid and aspartic acid were used in their neutral form.All illustrations were created using PYMOL 0.99rc6 . […]

Pipeline specifications

Software tools MODELLER, NAMD, PyMOL, PROPKA, PDB2PQR
Application Protein structure analysis
Organisms Mus musculus
Diseases Alzheimer Disease, Dementia, Neurodegenerative Diseases
Chemicals Zinc