title: Influence of PNA containing 8-aza-7-deazaadenine on structure stability and binding affinity of PNA·DNA duplex: insights from thermodynamics, counter ion, hydration and molecular dynamics analysis.
abstract: This paper describes the synthesis of a novel 8-aza-7-deazapurin-2,6-diamine (DPP)-containing peptide nucleic acid (PNA) monomer and Boc protecting group-based oligomerization of PNA, replacing adenine (A) with DPP monomers in the PNA strand. The PNA oligomers were synthesized against the biologically relevant SV40 promoter region (2494-AATTTTTTTTATTTA-2508) of pEGFP-N3 plasmid. The DPP-PNA·DNA duplex showed enhanced stability as compared to normal duplex (A-PNA·DNA). The electronic distribution of DPP monomer suggested that DPP had better electron donor properties over 2,6-diamino purine. UV melting and thermodynamic analysis revealed that the PNA oligomer containing a diaminopyrazolo(3,4-d)pyrimidine moiety (DPP) stabilized the PNA·DNA hybrids compared to A-PNA·DNA. DPP-PNA·DNA duplex showed higher water activity (Δnw = 38.5) in comparison to A-PNA·DNA duplex (Δnw = 14.5). The 50 ns molecular dynamics simulations of PNA·DNA duplex containing DPP or unmodified nucleobase-A showed average H-bond distances in the DPP-dT base pair of 2.90 Å (OH-N bond) and 2.91 Å (NH-N bond), which were comparably shorter than in the A-dT base pair, in which the average distances were 3.18 Å (OH-N bond) and 2.97 Å (NH-N bond), and there was one additional H-bond in the DPP-dT base pair of around 2.98 Å (O2H-N2 bond), supporting the higher stability of DPP-PNA·DNA. The analysis of molecular dynamics simulation data showed that the system binding free energy increased at a rate of approximately -4.5 kcal mol(-1) per DPP base of the PNA·DNA duplex. In summary, increased thermal stability, stronger hydrogen bonding and more stable conformation in the DPP-PNA·DNA duplex make it a better candidate as antisense/antigene therapeutic agents.
authors: Dr B. R. Ambedkar Center for Biomedical Research, Delhi, India. vtandon@acbr.du.ac.in
authors: Sharad K
authors: SK
authors: Gupta
authors: Souvik
authors: S
authors: Sur
authors: Rajendra
authors: R
authors: Prasad Ojha
authors: Vibha
authors: V
authors: Tandon
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D007477:Ions / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D020135:Peptide Nucleic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D007477:Ions; D020135:Peptide Nucleic Acids; C414764:8-aza-7-deazaadenine; D004247:DNA; D000225:Adenine