title: Theoretical study on steric effects of DNA phosphorothioation: B-helical destabilization in Rp-phosphorothioated DNA.
abstract: Phosphorothioation, with sulfur replacing a nonbridging oxygen of phosphate, has surfaced in bacterial DNA electrophoresis. To understand structural characteristics of the thio-substituted DNA, we have investigated the correlation between the relative energy of phosphate/phosphorothioate linkage and the backbone torsions. The relative energies (R.E.) computed by the quantum mechanical method, the PBE1PBE(CPCM, solvent=water)//PBE1PBE/6-31+G(2df) level of theory, were used to construct energy-scoring functions against backbone torsion variables, resulting in the squared correlation coefficients r(2) of 0.90-0.95. Then, the DNA energy alteration by phosphorothioation is estimated with the relative energy difference (ΔR.E.) between phosphate and phosphorothioate of the phosphate linkages in the DNA crystallographic database (NDB). As a result, Rp-phosphorothioation shifts the relative energy of B-helical structures by 2.7 ± 3.4 kcal/mol, destabilizing about 95% linkages, while Sp-phosphorothioation by -1.4 ± 2.4 kcal/mol, stabilizing over 84% linkages in the data sets. The B-helical destabilization is likely caused by the steric effect between the sulfur atom of Rp-phosphorothioate and the neighboring C-H groups of deoxyribose on the groove wall in B-helix. The unfavorable interaction may be magnified by the increasing rigidness of P-O-involving backbone torsions α and ζ upon the nonbridging phosphorothioations. Since B-helix is the most prevalent DNA double-helical structure and Rp-phosphorothioation is the exclusive configuration in bacteria thio-DNA found to date, the observed stereospecificity-destabilization correlation may reflect a structure-function relationship of biological DNA-phosphorothiation.
authors.affiliation: State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Liang
authors.forename: Peng
authors.initials: P
authors.lastname: Lian
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Han
authors.forename: Yifan
authors.initials: Y
authors.lastname: Chen
authors.forename: Linquan
authors.initials: L
authors.lastname: Bai
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.forename: Jingdan
authors.initials: J
authors.lastname: Liang
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
authors.forename: Yi-Lei
authors.initials: YL
authors.lastname: Zhao
mesh_terms: D004269:DNA, Bacterial / Q000737:chemistry*; D008962:Models, Theoretical; D009690:Nucleic Acid Conformation; D010710:Phosphates / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D004269:DNA, Bacterial; D010710:Phosphates; D014867:Water; C035638:thiophosphoric acid