Issue 16, 2022

Molecular recognition between bacterial phosphorothioate DNA and sulfur-binding domain (SBD): competition between the water cage and chalcogen-hydrophobic packet

Abstract

Bacterial DNA phosphorothioation (PT) physiologically and stereo-specifically replaces a non-bridging oxygen in a phosphate link with a sulfur atom, which can be recognized by a highly conserved sulfur-binding domain (SBD). Here we conducted thermodynamic integration (TI), molecular dynamics simulation, and quantum chemical calculations to decipher the specific molecular interactions between PT-DNA and SBD in Streptomyces coelicolor type IV restriction enzyme ScoMcrA. The TI-calculated binding affinity of (5′-CCGRp-PSGCCGG-3′)2 is larger than that of (5′-CCGGCCGG-3′)2 by about 7.4–7.7 kcal mol−1. The binding difference dominantly stems from hydration energy of non-phosphorothioate DNA (9.8–10.6 kcal mol−1) in aqueous solution, despite the persistent preference of 2.6–3.2 kcal mol−1 in the DNA–SBD MD simulations. Furthermore, the quantum chemical calculations reveal an unusual non-covalent interaction in the phosphorothioate-binding scenario, where the PS⋯NP165 chalcogen bond prevails the PS⋯HCβ vdW interactions from the adjacent residues H116–R117–Y164–P165–A168. Thus, the chalcogen–hydrophobic interaction pulls PT-DNA into the SBD binding pocket while the water cage pulls a normal DNA molecule out. The synergetic mechanism suggests the special roles of the proline pyrrolidine group in the SBD proteins, consistent with the experimental observations in the X-ray crystallography and structural bioinformatics analysis.

Graphical abstract: Molecular recognition between bacterial phosphorothioate DNA and sulfur-binding domain (SBD): competition between the water cage and chalcogen-hydrophobic packet

Supplementary files

Article information

Article type
Paper
Submitted
18 Jan 2022
Accepted
23 Mar 2022
First published
24 Mar 2022

Phys. Chem. Chem. Phys., 2022,24, 9176-9187

Molecular recognition between bacterial phosphorothioate DNA and sulfur-binding domain (SBD): competition between the water cage and chalcogen-hydrophobic packet

J. Li, H. Wan, H. Zhang, X. Wang, G. Liu, G. Wu, X. He, Z. Deng and Y. Zhao, Phys. Chem. Chem. Phys., 2022, 24, 9176 DOI: 10.1039/D2CP00291D

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