title: Theoretical study on the relationship between Rp-phosphorothioation and base-step in S-DNA: based on energetic and structural analysis.
abstract: Phosphorothioation (PT), previously used in synthetic antisense drugs to arrest the transcription or translation process, is also a novel physiological modification in bacteria DNAs. In the previous study, we reported that Rp-phosphorothioation (Rp-PT) destabilizes B-type helix significantly, using a quantum-mechanics-based energy scoring function developed with a dinucleotide model ( Zhang et al. J. Phys. Chem. B , 2012 , 116 , 10639 - 10648 ). A consequent question surfaces in the field of the phosphorothioated DNA (S-DNA) research: does the endogenous chemical modification interact with the base sequence in the bacterial genomes, e.g., in terms of the most common structure of the B-type helix? In this work, we carried out further energetic analysis on the backbone relative energies calculated with the scoring function according to 16 groups of base-step classifications. Moreover, we conducted molecular dynamics simulations of the B-helical structure with the different base-pair steps, to investigate the detailed structural changes upon the O-/S-substitution. As a result, the Rp-PT modification definitively enhances the stiffness of the backbone and differentiates backbone stability as an interaction with base-steps. Furthermore, certain exceptional sequences such as GT and CC were highlighted in the structural analysis of the sulfur local contacts and relative orientation of double strands, indicating that Rp-PT can cross-talk with particular base-steps. The special effects between the phosphorothioation and base-step may be related to the conservative consensus observed highly frequently in bacterial genomes.
authors.affiliation: State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , Shanghai 200240, China.
authors.forename: Limeng
authors.initials: L
authors.lastname: Chen
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Shi
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
authors.forename: Yi-Lei
authors.initials: YL
authors.lastname: Zhao
mesh_terms: D020029:Base Pairing; D059371:DNA, B-Form / Q000737:chemistry; D004269:DNA, Bacterial / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010100:Oxygen / Q000737:chemistry; D013455:Sulfur / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D059371:DNA, B-Form; D004269:DNA, Bacterial; D013455:Sulfur; D010100:Oxygen