Molecular Modeling of Single Beta-Sheet and the Beta-Sheet Stack of Amyloid Beta Protein 25 – 35
2011
Vita Duka, Cezary Czaplewsky, Victor Segalen, Inta Liepina

Amiloidosis is the misfolding of soluble proteins followed by their self-assembling, resulting in aggregation into insoluble fibrils which replace the functional cells or block the connectivity between the cells. The mechanism of amyloid formation is still unclear. The amyloid beta protein 1-42 is responsible for formation of human amyloidosis leading to Alzheimer disease. In the present work we studied the formation of amyloid β-structure of the amyloid beta protein fragment 25-35 (Abeta 25-35), GSNKGAIIGLM. A flat, parallel single six stranded beta-sheet (6Abeta 25-35) and ten stranded beta-sheet (10Abeta 25-35), as well as a stack built from six stranded beta-sheet (6x6Abeta 25-35) were simulated by molecular dynamics (MD) for 210 ns, 310 ns and 76 ns, respectively, using Amber 9.0 program package, f99 force field. Temperature was increased stepwise from 10K with the constant temperature platos at 200K and at 309 K. 6Abeta 25-35 and 10Abeta 25-35 single beta sheet systems show the stable ß-structure at 200K temperature, but collapse loosing ß-structure at 309K temperature, indicating that supplementary ß-sheets are required for ß-structure stabilization. The additional four strands in 10Abeta 25-35 comparing to 6Abeta 25-35 do not stabilize the β-sheet. In the 6x6Abeta 25-35 beta-sheet stack the strongest intra β-sheet interactions, which keeps the stack together, is comprised by Ile31 and Ile32 forming the main part of the hydrophobic core. Apart from that, in the β-sheet stack the β-sheets are kept together by Leu34 and Met35 hydrophobic interactions and Ser26 and Asn27 electrostatic interactions. In several cases the sidechain of Lys28 makes hydrogen bonds with the backbone carbonyl of Gly29 in the nearby β-sheet. The C-terminal part of the β-sheet stack is more prone to keep the β-sheet structure while the N-terminal part of the β-sheet stack is more flexible which is in accord with the experimental data [39]. A single strand of the Abeta 25-35 stack tends to jump away from the stack and turns from ß-structure to coil conformation with the further perspective to turn to α-helix. This is in accordance with literature data suggesting that the Abeta 25-35 peptide could form both β-structure and α-helical structure in water and membrane environment depending on conditions [38].


Atslēgas vārdi
Amyloid beta protein, Abeta, amyloidosis, molecular dynamics, beta-sheet

Duka, V., Czaplewsky, C., segalen, V., Liepina, I. Molecular Modeling of Single Beta-Sheet and the Beta-Sheet Stack of Amyloid Beta Protein 25 – 35. Materiālzinātne un lietišķā ķīmija . Nr.23, 2011, 62.-72.lpp. ISSN 1407-7353.

Publikācijas valoda
English (en)
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