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This article is part of the supplement: The 2008 International Conference on Bioinformatics & Computational Biology (BIOCOMP'08)

Open Access Research

Comparing 2-nt 3' overhangs against blunt-ended siRNAs: a systems biology based study

Preetam Ghosh1*, Robert Dullea2, James E Fischer2, Tom G Turi5, Ronald W Sarver3, Chaoyang Zhang1, Kalyan Basu4, Sajal K Das4 and Bradley W Poland2

Author Affiliations

1 School of Computing, The University of Southern Mississippi, 118 College Drive, Hattiesburg, MS-39406, USA

2 EMS Computational Sciences, Pfizer Inc., PGRD-Groton Laboratories, Eastern Point Road, Groton, CT-06340, USA

3 EMS Protein Cell and Assay Technology, Pfizer Inc., PGRD-Groton Laboratories, Eastern Point Road, Groton, CT-06340, USA

4 Department of Computer Science & Engineering, The University of Texas at Arlington. 416 Yates St., Arlington, TX-76019, USA

5 Covance Central Labs, 8211 Scicor Dr, Indianapolis, IN-46214, USA

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BMC Genomics 2009, 10(Suppl 1):S17  doi:10.1186/1471-2164-10-S1-S17

Published: 7 July 2009

Abstract

In this study, we formulate a computational reaction model following a chemical kinetic theory approach to predict the binding rate constant for the siRNA-RISC complex formation reaction. The model allowed us to study the potency difference between 2-nt 3' overhangs against blunt-ended siRNA molecules in an RNA interference (RNAi) system. The rate constant predicted by this model was fed into a stochastic simulation of the RNAi system (using the Gillespie stochastic simulator) to study the overall potency effect. We observed that the stochasticity in the transcription/translation machinery has no observable effects in the RNAi pathway. Sustained gene silencing using siRNAs can be achieved only if there is a way to replenish the dsRNA molecules in the cell. Initial findings show about 1.5 times more blunt-ended molecules will be required to keep the mRNA at the same reduced level compared to the 2-nt overhang siRNAs. However, the mRNA levels jump back to saturation after a longer time when blunt-ended siRNAs are used. We found that the siRNA-RISC complex formation reaction rate was 2 times slower when blunt-ended molecules were used pointing to the fact that the presence of the 2-nt overhangs has a greater effect on the reaction in which the bound RISC complex cleaves the mRNA.