title: Energetically important C-H···F-C pseudohydrogen bonding in water: evidence and application to rational design of oligonucleotides with high binding affinity.
abstract: 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.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 2K6.
authors.forename: Maryam Yahyaee
authors.initials: MY
authors.lastname: Anzahaee
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Watts
authors.forename: Nageswara R
authors.initials: NR
authors.lastname: Alla
authors.forename: Allen W
authors.initials: AW
authors.lastname: Nicholson
authors.forename: Masad J
authors.initials: MJ
authors.lastname: Damha
mesh_terms: D001483:Base Sequence; D015195:Drug Design; D006860:Hydrogen Bonding; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009841:Oligonucleotides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D044366:Transition Temperature; D014867:Water / Q000737:chemistry*
chemical_list: D009841:Oligonucleotides; D014867:Water