Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Inhibition of Aβ aggregation in Alzheimer's disease using the poly-ion short single stranded DNA: In silico Study
Alzheimer's disease (AD) is currently one of the most common form of senile dementia connected with amyloid beta peptide (Aβ) accumulation in human brain tissue (Hardy, J. & Selkoe, D.J, 2002). Aβ peptide undergoes conformational transitions leading to aggregation prone structures that drives the self-assembly to form soluble oligomers and eventually insoluble amyloid fibrils when transferred from the transmembrane phase to the physiological aqueous phase. Most of the experimental techniques do not possess the temporal and spatial resolution to yield atomistically detailed information about the seed structure of Aβ peptide conformation responsible for initiating the aggregation. So in this study we carried out fully atomistic molecular dynamics simulations to understand the structural features of Aβ protein that seed aggregation. The initial structure of Aβ1-42 peptide [PDB ID: 1IYT] for the MD simulation was taken from the PDB ( H M Berman, J Westbrook, Z Feng, G Gilliland, T.N Bhat, H Weissig, I N Shindyalov, P E Bounel, 1999 ). The initial structure was then edited, solvated explicitly using TIP3P water model, made neutral by adding counter ions and then subjected to minimization, equilibration and finally the production run for 64 ns. In this simulation study we used ff99SB (V. Hornak, R. Abel, A. Okur, B. Strockbine, A. Roitberg, and C. Simmerling, 2006) Amber force field. We then carried out the dynamics of Aβ1-42 peptide in the presence of poly-ion, single stranded DNA (5'-AAAGAGAGAGAG-3'). The poly-ion, ssDNA (because of charge difference) showed electrostatic attraction towards the Aβ1-42 peptide which has significant number of positively charged amino acids in it. As a result we observed that the Aβ1-42 peptide was wrapped (encapsulated) by the ssDNA. Because of this, we found that the other unit of Aβ1-42 peptide faces difficulty to approach the encapsulated Aβ
Figure 1: Structure showing encapsulation of amyloid beta peptide by ss-DNA
H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I. N. Shindyalov, P. E. Bounel. (1999). Nucleic Acid Research, 28, 235-242.
V. Hornak, R. Abel, A. Okur, B. Strockbine, A. Roitberg, and C. Simmerling, (2006). Bioinformatics, 65 (3), 712-725.
Department of Molecular Biology and Biotechnology