The structure and dynamic properties of different antisense related duplexes (DNA.RNA, 2'O-Me-DNA.RNA, 2'F-ANA.RNA, C5(Y)-propynyl-DNA. RNA, ANA.RNA, and control duplexes DNA.DNA and RNA.RNA) have been determined by means of long molecular dynamics simulations (covering more than 0.5 mu s of fully solvated unrestrained MD simulation). The massive analysis presented here allows us to determine the subtle differences between the different duplexes, which in all cases pertain to the same structural family. This analysis provides information on the molecular determinants that allow RNase H to recognize and degrade some of these duplexes, whereas others with apparently similar conformations are not affected. Subtle structural and deformability features define the key properties used by RNase H to discriminate between duplexes.