Theoretical Study on Steric Effects of DNA Phosphorothioation: B-Helical Destabilization in Rp-Phosphorothioated DNA

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• 作者：Yi-Chao Zhang ; Juan Liang ; Peng Lian ; Yiwen Han ; Yifan Chen ; Linquan Bai ; Zhijun Wang ; Jingdan Liang ; Zixin Deng ; Yi-Lei Zhao
• 刊名：The Journal of Physical Chemistry B
• 出版年：2012
• 出版时间：September 6, 2012
• 年：2012
• 卷：116
• 期：35
• 页码：10639-10648
• 全文大小：594K
• 年卷期：v.116,no.35(September 6, 2012)
• ISSN：1520-5207

文摘

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 r² of 0.90鈥?.95. Then, the DNA energy alteration by phosphorothioation is estimated with the relative energy difference (螖R.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 卤 3.4 kcal/mol, destabilizing about 95% linkages, while Sp-phosphorothioation by 鈭?.4 卤 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鈥揌 groups of deoxyribose on the groove wall in B-helix. The unfavorable interaction may be magnified by the increasing rigidness of P鈥揙-involving backbone torsions 伪 and 味 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鈥揻unction relationship of biological DNA-phosphorothiation.