Conformational behavior of beta amyloids and their interactions with cholesterol derivatives

Zdeněk Kříž¹, Zdena Krištofíková², Jaroslav Koča¹

¹National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic, zdenek@chemi.muni.cz

²Prague Psychiatric Centre, Ústavní 91, 181 03 Praha 8 – Bohnice, Czech Republic

Proteins play a critical role in most cellular processes, from signal transduction to enzyme catalysis. Folding to the correct three-dimensional native state is crucial to their function. Under pathological conditions, proteins can misfold, typically to structures in which the hydrophobic residues, which form the hydrophobic core of the folded protein, are exposed to the solvent. These misfolded proteins can self-assemble into a variety of aggregate structures, including large, insoluble fibrillar entities known as amyloids. A number of diseases, including Alzheimer´s disease (AD) and type II diabetes, are associated with the presence of amyloid [1]. Extracellular proteic plaques found in the brains of patients affected by Alzheimer´s disease contain fibrils composed of β-amyloid (Aβ) peptides. These range in length from 39 to 43 amino acids, the most abundant form being Aβ-(1-42). The Aβ-(1-42) peptide nucleates and aggregates more rapidly than shorter Aβ peptides [2,3]. It indicates that the C-terminus sequence is critical for the nucleation of amyloid formation and suggesting that production of Aβ-(1-42) may be pathogenic.

Recently we have performed series of MD simulations on rat and human amyloid beta. The AMBER molecular modeling package was used for MD simulations and analyses of results. The NMR solved structure of human Aβ-(1-42) peptide from the PDB database (pdb code 1z0q) was used as starting point of the simulations. The rat Aβ-(1-42) peptide have been prepared using the Triton and Modeller software from human Aβ-(1-42) peptide by in silico mutation method. Each molecule was immersed into octahedral simulating box with TIP3P water molecules (minimal thickness of water layer was 12 A) and counter ions were added to neutralize electrostatic charge of the molecule. We prepared three different simulation conditions with concetration of NaCl 0.00, 0.15 and 0.30 mol/l. The AMBER force field ff03 was used for all simulations. The snapshots from the trajectories were used for docking studies of interactions with 24S-hydroxycholesterol – cerebrosterol. The docking studies have been performed by the DOCK 6.3 software[4].

The results show the differences in conformational behavior of peptides in solvent with different ionic strength and different ability to interact with cholesterol derivatives.

This work has been supported by the Czech Science Foundation (305/09/0457) and by the Ministry of Education of the Czech Republic (MSM0021622413, LC06030). The access to the METACentrum supercomputing facilities provided under the research intent MSM6383917201 is highly appreciated.

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