THE AFFINITY OF AN OLIGODEOXYNUCLEOTIDE PEPTIDE CONJUGATE FOR AN RNA HAIRPIN LOOP DEPENDS ON STEREOCHEMISTRY AT THE DNA PEPTIDE JUNCTION

Molecular models of an oligodeoxynucleotide-peptide conjugate complexe d to an RNA hairpin loop were constructed to assess the effect of ster eoisomerism at the point of attachment of the peptide to the oligodeox ynucleotide on the affinity of the conjugate for an RNA target. The pe ptide portion of the oligodeoxynucleotide-peptide conjugate, (L-lysine )(8), was covalently attached to the N-allyl group of (D)- or (L)-aspa rtic alcohol that was incorporated into the interior of an antisense o ligodeoxynucleotide. The stereocenter in the oligodeoxynucleotide inte rior originates from either (D)- or (L)-aspartic alcohol. The oligodeo xynucleotide portion of the oligodeoxynucleotide-peptide conjugate for ms Watson-Crick base pairs with the single-stranded RNA that flanks th e RNA hairpin loop. The positively charged peptide makes specific elec trostatic contacts with the negatively charged phosphate backbone of t he RNA hairpin loop when attached to the N-allyl of (D)-aspartic alcoh ol but does not have the proper orientation to make these electrostati c contacts when attached to the N-allyl of (L)-aspartic alcohol. This modelling study emphasizes the importance of stereocontrol at the poin t of branching in synthesizing oligodeoxynucleotide-peptide conjugates for binding of RNA hairpin loops.