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Flap sub-domain dynamics of serine-threonine phosphatase (Stp1) of Staphylococcus aureus: an accelerated molecular
Pranabesh Mandal1, Priyanka Rani1, Girish Chandra1
1Department of Bioinformatics, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, India.
Abstract:
Vancomycin and daptomycin are commonly used glycopeptide antibiotics to cure Gram-positive staphylococcal infections. The clinical isolates of mutant Staphylococcus aureus strains, Methicillin-Resistant (MRSA) and Vancomycin-Resistant (VRSA), have developed resistance against these antibiotics. A recently discovered Serine/threonine phosphatase (Stp1) is an Mn+2 containing protein at the active site with a flap sub-domain that participates in the phospho-signaling system of bacterial cell wall formation. The flap sub-domain probably regulates substrates recruitment and release with an extra Mn+2, possibly highly flexible as in the other homologous family of proteins. In this study, the flap sub-domain has been sampled with conventional and accelerated molecular dynamics (cMD and aMD) simulations to get other sub-optimal conformational states of the protein that are nearly impossible to observe through experimental methods. Trajectory analysis has shown that protein remained static in cMD while dynamic in aMD with RMSD of ∼2Å and ∼3Å, respectively. Accelerated MD has shown greater flexibility of ∼4 Å in the flap sub-domain, while cMD only captured a deviation of ∼ 2 Å. Later, the dynamic cross-correlation map (DCCM) confirmed that the flap sub-domain is significantly more flexible than the other part of the structure, indicating its role in substrate regulation. Secondary structure transition in the flap sub-domain, i.e. 3-10 helix and turn (PRO159 - ILE163) region of the flap sub-domain shifted into α-helix, which is a more stable structure. Further, the trajectory has been clustered, and conformational states extracted, which may be exploited in structure-based antibiotics discovery.Communicated by Ramaswamy H. Sarma.
Insights
Researchers studied Staphylococcus aureus
Area of Science:
- Microbiology
- Structural Biology
- Computational Biology
Background:
- Methicillin-Resistant (MRSA) and Vancomycin-Resistant (VRSA) strains of *Staphylococcus aureus* exhibit resistance to common antibiotics like vancomycin and daptomycin.
- Serine/threonine phosphatase (Stp1) is crucial for bacterial cell wall formation and possesses a flexible flap sub-domain potentially involved in substrate regulation.
Purpose of the Study:
- To investigate the conformational dynamics of the Stp1 flap sub-domain using molecular dynamics simulations.
- To identify novel conformational states of Stp1 for structure-based antibiotic discovery against resistant bacterial strains.
Main Methods:
- Conventional molecular dynamics (cMD) and accelerated molecular dynamics (aMD) simulations were employed to sample protein conformational states.
- Trajectory analysis, including Root Mean Square Deviation (RMSD) and dynamic cross-correlation map (DCCM), was used to assess protein flexibility.
- Clustering analysis was performed on simulation trajectories to extract distinct conformational states.
Main Results:
- Accelerated MD revealed significantly greater flexibility (∼4 Å) in the Stp1 flap sub-domain compared to cMD (∼2 Å).
- DCCM analysis confirmed the flap sub-domain's enhanced flexibility, supporting its role in substrate recruitment and release.
- A secondary structure transition from 3-10 helix/turn to a more stable α-helix was observed in the flap sub-domain.
Conclusions:
- The Stp1 flap sub-domain exhibits significant flexibility crucial for its function in phospho-signaling pathways.
- Accelerated MD simulations provide valuable insights into protein dynamics not easily obtainable through experimental methods.
- The identified conformational states of Stp1 offer potential targets for developing new antibiotics against resistant *Staphylococcus aureus*.
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