Lynx Therapeutics has developed a class of compounds, phosphoramidates ODNs that exhibit increased duplex stability. At present a key difficulty is that the improvements proceed mainly by trial and error, due to a lack of complete understanding of how the modifications affect duplex stability. During Phase I of the STTR, workers at Lynx and Colvin at Livermore intent to systematically study ODN modifications through integrated experiments and computer modeling. As Lynx synthesizes and measures the hybridization properties of new modifications, the academic applicant will compute free energies through molecular dynamics (MD) simulations, model DNA-RNA duplex melting through high-temperature MD, and calculate relative pKa shifts through quantum chemical calculations. Improved ODNs will be assayed against human diseases in Phase II of this project.
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