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

Abstract

Triple helix formation by oligonucleotides can be extended beyond polypurine tracts with the help of specially designed linkers. In this paper we focus our attention on the integrase-binding site of the HIV-1 virus located on the U5 LTR end which contains two adjacent purine tracts on opposite strands. Two alternate triple helices with a 3'-3' junction 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, both in vacuo and in aqua. The non-isomorphism of the triplets in the GpT steps in the first sequence, gives rise to non canonical conformations in the torsion angles, hydration appears to be crucial for this triplex. Sugar puckers are predominantly South during in vacuo simulations while they turn East in aqua. In the simulation in aqua the triplexes are shrouded by an hydration shell, however, we have not been able to detect any permanent hydrogen bond bridge between DNA and water. The solvation of ions as well as their radial distribution, appear to be relatively well behaved despite the artifacts known to be generated by the simulation procedure. The experimental feasibility of these structures is discussed.

HIV integrase: a target for drug discovery

“…Short oligonucleotides also inhibit HIV IN, although their mode of inhibition is different. Firstly, it has been shown that a short single-stranded oligonucleotide targets a purine-rich motif in the viral longterminal-repeat ends, which leads to the formation of a DNA triple helix [149][150][151][152]. Secondly, oligonucleotides made up from deoxyguanosine and thymidine are potent IN inhibitors, with IC 50 values in the nanomolar range [70].…”

Branched oligonucleotide‐intercalator conjugate forming a parallel stranded structure inhibits HIV‐1 integrase

“…Two different mechanisms have been previously summoned to explain integrase inhibition by (G,A)‐ and (G,T)‐containing oligonucleotides: The first one involves formation of a short triple‐helix on the viral DNA extremity spanning over the integrase binding site. This hypothesis was first considered since a molecular modelling study suggested that the branched oligonucleotide OPC‐5′‐GGAAAA3′‐(CHOH) 3 ‐3′‐AGAGA‐5′‐OPC may form a thermodynamically stable triple helix on the U5 sequence [17]. To address that possibility, GA‐OPC 2 was assayed on the 3′‐processing of either a mutated LTR U5 extremity or the U3 DNA extremity (see Fig.…”

Beyond nucleic acid base pairs: From triads to heptads

“…Before these studies are discussed in more detail, molecular dynamics simulations on polyad‐containing structures are to be listed, however, for the reasons mentioned above. Simulations have been performed for triplexes135–142 and quadruplexes 31, 32, 143–147. In addition, more and more structural diverse RNA structures are studied.…”