From Rational Design of Drug Crystals to Understanding of Nucleic Acid Structures: Lamivudine Duplex

A DNA-like duplex of nucleosides is probable to exist even without the 5`-phosphate groups needed to assemble the chain backbone. However, double-stranded helical structures of nucleosides are unknown. Here, we report a duplex of nucleoside analogs that is spontaneously assembled due to stacking of the neutral and protonated molecules of lamivudine, a nucleoside reverse transcriptase inhibitor (NTRI) widely used in anti-HIV drug combinatory medication. The left-handed lamivudine duplex has features similar to those of i-motif DNA, as the face-to-face base stacking and the helix rise per base pair. Furthermore, the protonation pattern on alternate bases expected for it DNA-like duplex stabilized by pairing of neutral and protonated cytosine fragments was observed for the first time in the lamivudine double-stranded helix. This structure demonstrates that hydrogen bonds can substitute for covalent phosphodiester linkage in the stabilization of the duplex backbone. This interesting example of spontaneous molecular self-organization indicates that the 5`-phosphate group could not be a requirement for duplex assembly.

CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)[2007/07185-5]

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)

FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais)[APQ-2011-5.02/07]

FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais)[APQ-6010-5.02/07]

Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)

FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais)[APQ-02685-09]

Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)

CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)[PNPD2008]

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)