LNA substitutions should be useful for probing RNA with short 2 0 -O-methyl RNA oligonucleotides RNA structure can be probed with short oligonucleotides on microarrays (3) . To optimize such methods, it is necessary to have tight binding that is sequence independent and that discriminates against mismatches. It appears that LNA nucleotides can be used to achieve this. For example, free energy increments for 2 0 -O-methyl RNA/RNA nearest neighbors range from À0.7 to À3.5 kcal/mol, corresponding to 5 0 A M U M /3 0 UA and 5 0 G M C M /3 0 CG, respectively ( Table 4 ). The average increment of À1.3 kcal/mol of internal and 3 0 terminal LNA can help compensate for such less favorable stability of AU relative to GC pairs. The stability enhancement from LNA can also allow the use of shorter oligonucleotides.