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J Am Chem Soc. 2011 Feb 2;133(4):728-31. doi: 10.1021/ja109817p. Epub 2010 Dec 20.

Energetically important C-H···F-C pseudohydrogen bonding in water: evidence and application to rational design of oligonucleotides with high binding affinity.

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Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 2K6.


It is controversial whether organic fluorine can form energetically important hydrogen bonds in aqueous environments. We previously showed by NMR and molecular modeling that the unexpectedly high binding affinity of 2'F-ANA is largely due to a C-H···F-C pseudohydrogen bond at pyrimidine-purine steps. Comparisons of the melting of duplexes with identical sequence composition but a rearranged sequence confirm that energetically important fluorine-mediated pseudohydrogen bonding is in operation in these sequences. The effect is of particular importance when the H-bond donor (purine H8) is activated by the presence of fluorine at its own 2'-position. These results provide a rational method to increase the binding affinity of antisense oligonucleotides by placement of 2'F-ANA modifications at pyrimidine-purine steps.

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