Molecular-Dynamics Studies of Single-Stranded Hexitol, Altritol, Mannitol, and Ribose Nucleic Acids (HNA, MNA, ANA, and RNA, Resp.) and of the Stability of HNA⋅RNA, ANA⋅RNA, and MNA⋅RNA Duplexes

Abstract

The influence of the orientation of a 3′-OH group on the conformation and stability of hexitol oligonucleotides in complexes with RNA and as single strands in aqueous solution was investigated by molecular-dynamics (MD) simulations with AMBER 4.1. The particle mesh Ewald (PME) method was used for the treatment of long-range electrostatic interactions. An equatorial orientation of the 3′-OH group in the single-stranded D-mannitol nucleic acid (MNA) m(GCGTAGCG) and in the complex with the RNA r(CGCAUCGC) has an unfavorable influence on the helical stability. Frequent H-bonds between the 3′-OH group and the O−C(6′) of the phosphate backbone of the following nucleotide explain the distorted conformation of the MNA⋅RNA complex as well as that of the single MNA strand. This is consistent with experimental results that show lowered hybridization potentials for MNA⋅RNA complexes. An axial orientation of the 3′-OH group in the D-altritol nucleic acid (ANA) a(GCGTAGCG) leads to a stable complex with the complementary RNA r(CGCAUCGC), as well as to a more highly preorganized single-stranded ANA chain. The averaged conformation of the ANA⋅RNA complex is similar to that of A-RNA, with only minor changes in groove width, helical curvature, and H-bonding pattern. The relative stabilities of ANA⋅RNA vs. HNA⋅RNA (HNA=D-hexitol nucleic acid without 3′-OH group) can be explained by differences in restricted movements, H-bonds, and solvation effects.