Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
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 peptide to form dimer. But the extent of wrapping depends on the size of ssDNA and the type of Aβ peptide considered. From our findings we see this method to be significant method to inhibit the Aβ peptide aggregation at an early stage and also to disassemble the amyloid fibrils and thereby reduce the risk of Alzheimer's disease.


Figure 1: Structure showing encapsulation of amyloid beta peptide by ss-DNA

    J. Hardy & D.J. Selkoe. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356.

    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.

Mary Dutta
Mattaparthi Venkata Satish Kumar

Department of Molecular Biology and Biotechnology
Tezpur University,
Tezpur-784 028, ASSAM, INDIA

Ph.: +918721841782