Publication details
Investigating effect of ionic strength on conformational behavior of beta amyloids
| Authors | |
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| Year of publication | 2009 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Motivation: Extracellular proteic plaques found in the brains of patients affected by Alzheimers disease contain fibrils composed of beta-amyloid (Abeta) peptides. These range in length from 39 to 43 amino acids, the most abundant form being Abeta-(1-42). The Abeta-(1-42) peptide nucleates and aggregates more rapidly than shorter Abeta peptides [1-3]. It indicates that the C-terminus sequence is critical for the nucleation of amyloid formation and suggesting that production of Abeta-(1-42) may be pathogenic. Although human and rat Abeta-(1-42) peptides differ only by 3 amino acids (positions 5, 10 and 13), they show different cerebral deposition during aging [4]. It indicates the differences in conformational behavior of both peptides. We have performed long range molecular dynamics simulations of both peptides in explicit solvent with different ionic strength. The stability of the secondary structures of the peptides and formation of intramolecular hydrogen bonds were investigated. Methods: The AMBER molecular modeling package was used for MD simulations and analyses of results. The NMR solved structure of human Abeta-(1-42) peptide from the PDB database (pdb code 1z0q) was used as starting point of the simulations. The rat Abeta-(1-42) peptide have been prepared using the Triton and Modeller software from human Abeta-(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. There were added only 3 Na+ ions to the simulation box. In the second case 11 chlorine and 11 sodium ions were added into the box, which corresponds to physiological concentration of 0.15 mol.dm-3 NaCl. The AMBER force field ff03 was used for all simulations. Results: Calculated radii of gyration show similar values for all studied systems.The end-to-end distance analyses similar behavior for both human Abeta simulations (distance about 20 A) and also for both rat Abeta systems (distance about 10 A). It has been found very stable alpha-helical core (residues 10 to 21) which contains the central hydrophobic core. Human Abeta in 0 ionic strength shows small not very stable beta-sheets located near the C-end, but in the physiological conditions the C-end of the human Abeta shows higher instability with random secondary structure elements. Rat Abeta in 0 ionic strength shows second smaller pi-helix at the C-end with relatively high stability, but in the physiological conditions this helix is unstable and small beta-sheets at the C-end with lower stability were found in the simulation. |
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