A MOLECULAR MECHANICS AND DYNAMICS STUDY OF ALTERNATE TRIPLE-HELICES INVOLVING THE INTEGRASE-BINDING SITE OF THE HIV-1 VIRUS AND OLIGONUCLEOTIDES HAVING A 3'-3' INTERNUCLEOTIDE JUNCTION

Triple helix formation by oligonucleotides can be extended beyond poly purine tracts with the help of specially designed linkers. In this pap er we focus our attention on the integrase-binding site of the HIV-1 v irus located on the U5 LTR end which contains two adjacent purine trac ts on opposite strands. Two alternate triple helices with a 3'-3'junct ion in the third strand are considered: 5'-GGTTTTp3'-3'pTGTGT-5' and 5 '-GGAAAAp3'-3'pAGAGA-5' The structural plausibility of these triplexes is investigated using molecular mechanics and dynamics simulations, b oth in vacuo and in aqua. The non-isomorphism of the triplets in the G pT steps in the first sequence, gives rise to non canonical conformati ons in the torsion angles, hydration appears to be crucial for this tr ipler. Sugar puckers are predominantly South during in vacuo simulatio ns while they turn East in aqua. In the simulation in aqua the triplex es are shrouded by an hydration shell, however, we have not been able to detect any permanent hydrogen bond bridge between DNA and water. Th e solvation of ions as well as their radial distribution, appear to be relatively well behaved despite the artifacts known to be generated b y the simulation procedure. The experimental feasibility of these stru ctures is discussed.