Investigação computacional da INHHQ como atenuante da interação metal-proteína na proteína beta amiloide

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of cognitive abilities affecting memory, language, logical thinking and other capacities related to the brain. On the molecular view, it is observed large deposits of extracellular senile plaques formed by amyloid beta peptide (Ab) and intracellular neurofibrillary tangles formed by tau protein. The metals iron, zinc and copper are also found in high concentrations in the plaques. The metallic hypothesis is based on the role of these metals, which enhance Ab precipitation in in vitro experiments and on the redox activity of iron and copper, which can form reactive oxygen species (ROS). The metal-protein attenuating compounds (MPAC) emerged as a class of compounds able to reduce metal concentration, where they could act reaching the metallic site in the peptide and redistribute the metals after coordination through the brain, reestablishing the metallic homeostasis. Hauser-Davis et al. (2015) firstly described the ligand INHHQ (isonicotinoyl hydrazone of 8-hydroxyquinoline-2-carboxaldehyde) as a potential MPAC candidate, as it showed great ability to bind to zinc(II) and copper(II) compared to Ab. INHHQ was also tested with -synuclein, a protein associated with Parkinson’s disease, and showed great results removing copper(I) and copper(II) ions from the protein structure. These results contribute to increase the interest in a better description of its function as a MPAC. The present work aimed to propose and evaluate a mechanism of action of INHHQ as an MPAC for zinc coordinated to Ab. Two mimetic models were created for the quantum calculations (QM) to obtain the energies involved in each step of the mechanism. Molecular dynamics simulations were also used and the whole peptide was simulated in different steps of the mechanism. The INHHQ structure is very flexible on the dynamics simulation, what indicates its ability to dock on the Ab structure. The formation of the zinc complex [Zn(INHHQ)(H2O)2]2+ was also studied and its free energy of formation showed a very spontaneous reaction with G = -14,335 kcal mol-1. The simulations with INHHQ and the peptide clearly point towards weak interactions between the species, which maintain both interacting through hydrophobic and -stacking interactions. Only few hydrogen bonds were formed between the ligand and Ab. For both QM models the adduct formation is the thermodynamically less favorable step with G = +23,87 kcal mol-1 obtained for one of the models. This same model showed a global energy of G = +11,73 kcal mol-1, what makes it a feasible process to occur in the biological environment.