Hybridization of oligonucleotides to RNA is important for applications, such as antisense therapeutics (4, 8, 21, 46, (52) (53) (54) , diagnostics (32, 33, 42, 55) , profiling gene expression with microarrays (18) (19) (20) 56) , identifying bands by Northern blots of gels (57, 58) and probing RNA structure (1, 3, 15, (59) (60) (61) . Oligonucleotides with 2 0 -O-alkyl modifications can be particularly useful for these applications because they are easily synthesized (39, 43) , chemically stable and bind relatively tightly to RNA (39) (40) (41) (42) . However, for many applications, it is desirable to modulate the binding affinity. For example, sequence independent duplex stabilities would benefit applications that involve multiplex detection, such as microarrays.