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Master sporulation-regulatory protein Spo0A binds to the cognate DNA sequence 5'-TGTCGAA-3' (0 A-box) and control transcription of hundreds of genes in sporulating Bacilli. Thus, discrimination of similar near-cognate 0 A-box sequences (differing by a single base pair) by Spo0A is critical for accurate transcriptional control. The thermodynamics underlying the 0 A-box recognition by Spo0A is unknown. Recent X-ray structure of Spo0A from Bacillus subtilis in complex with cognate 0 A-box DNA sequence not only revealed the intricate atomic interaction network related to transcription activation but also provide an opportunity of directly computing the energetics of 0 A-box selectivity by Spo0A. Using the X-ray structure of cognate Spo0A-DNA complex as a template, we report computer simulations that quantitatively estimated the relative binding free energies of Spo0A to cognate and near-cognate 0 A-box sequences in B. subtilis. The results show that the strength of Spo0A binding preference for cognate 0 A-box sequence relative to its near-cognate analogue varies drastically along the location of the mismatch (5'→ 3') in the 0 A-box sequence. Spo0A selectivity in favour of the cognate sequence is ensured by the loss of protein-DNA major groove interactions and/solvent exposure of the hydrophobic pockets in the near-cognate Spo0A-DNA complexes. The calculations provide a clue about the energetics of Spo0A discrimination between cognate and near-cognate 0 A-box sequences and its link to 3 D structures, which ensure fidelity of transcription initiation in B. subtilis.Communicated by Ramaswamy H. Sarma.

Citation

Saransh Shukla, Amit Kumar, Debasish Das, Priyadarshi Satpati. Principle of DNA recognition by sporulation-regulatory protein (Spo0A) in Bacillus subtilis. Journal of biomolecular structure & dynamics. 2020 Oct;38(17):5186-5194

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PMID: 31760912

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