The database in Tables 1 and 2 is too small to The magnitude and sequence dependence of the stabilization due to LNAs are surprising. Ribose and therefore probably 2 0 -O-methyl ribose sugars in single strands are typically found in roughly equal fractions in C2 0 -endo and C3 0 -endo conformations. If the methylene bridge of an LNA only locks the sugar into the C3 0 -endo conformation, then the expected stabilization due to preorganization would be: DDG ¼ ÀRT ln 2, which is À0.4 kcal/mol at 37 C (310.15 K). The stabilization observed for a 5 0 terminal LNA is roughly À0.4 kcal/ mol, but the average stabilizations for internal LNAs and 3 0 terminal A L , C L and G L are more favorable at À1.3 and À1.2 kcal/mol, respectively. Moreover, if stabilization was only due to preorganization of an LNA sugar, then the effect would not saturate when alternate sugars are LNA. Evidently, the LNA substitution also affects the 5 0 neighboring base pair in a way that enhances the stabilization beyond that expected from preorganization of a single sugar. Interestingly, NMR structures of DNA/LNA chimeras bound to RNA show that only the DNA sugar 3 0 of the LNA is driven to a C3 0endo conformation for the sequence d(5 0 CTGAT L ATGC)/ 3 0 GACUAUACG, but all non-terminal DNA sugars are C3 0 -endo when all three Ts are LNAs (76) . The free energy increments at 37 C for LNA substitutions ranged from +0.83 to À1.90 kcal/mol with an average of À0.55 kcal/mol. This compares with a range from +0.18 to À2.17 kcal/mol and an average of À1.32 kcal/mol for the single internal LNA substitutions in Table 1 . The comparision suggests that single LNA substitutions are on average more stabilizing to 2 0 -O-methyl RNA/RNA duplexes than to DNA/DNA duplexes. This may reflect the expectation that LNA substitutions do not have a large effect on the conformations of 2 0 -O-methyl RNA/RNA duplexes, but alter the conformations of DNA/DNA duplexes.