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Mechanistic insights from molecular dynamic simulation of Rv0045c esterase in Mycobacterium tuberculosis

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Abstract

Rv0045c is an esterase involved in lipid metabolism of Mycobacterium tuberculosis. It belongs to the α/β hydrolase family. In the current study, we performed sequence- and structure-based analysis of Rv0045c followed by molecular dynamics (MD) simulation for 100 ns to investigate conformational changes in the enzyme. Sequence analysis revealed that this enzyme is possibly a hormone-sensitive lipase. Further, through structural analysis, a putative catalytic tetrad containing “Ser-Asp-Ser-His” and residues involved in the formation of an oxyanion hole were identified. MD simulation of Rv0045c revealed a conformational transition from an open to a closed state. The active site pocket was found to be gated by four loops. The potential role of the cap domain and the mobile histidine is discussed. From the simulation, we see that the conformational changes mimic the different stages in the reaction mechanism of Rv0045c. These results support the hypothesis that free enzyme simulation encompasses all the conformations necessary for the different stages of catalysis. Our findings add to the growing knowledge of an important family of esterases in Mycobacterium tuberculosis.

Sequence and structural analysis of Rv0045c

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Acknowledgment

The authors thank the Biotechnology Information System (BTIS), Department of Biotechnology for computational facilities.

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Authors and Affiliations

  1. Center for Biotechnology, Anna University, Chennai, 600 025, India

    Durairaj Sherlin & Sharmila Anishetty

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  1. Durairaj Sherlin
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  2. Sharmila Anishetty
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Corresponding author

Correspondence to Sharmila Anishetty.

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ESM 1

(PDF 1014 kb)

The video shows the transition from open to closed state. The structure of Rv0045c is shown in surface representation and colored cyan, the active site region is red, the gating loop 190–205 is in magenta, loop 221–225 in orange, loop 278–284 in green and loop 305–310 in blue. (MP4 7853 kb)

Movie S2

The video showing the movement of the gating loops and the histidine flipping during the transition from open to close state. The structure of Rv0045c is shown in cartoon representation, the surface loops responsible for the closure loop 190–205 is in yellow, loop 221–225 is in blue, loop 278–284 in magenta and loop 305–310 in orange. The catalytic triad is shown in stick representation and coloured red. (MP4 8009 kb)

The video shows the close up view of catalytic histidine undergoing flipping (for clarity only the catalytic residues are shown). (MP4 9649 kb)

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Sherlin, D., Anishetty, S. Mechanistic insights from molecular dynamic simulation of Rv0045c esterase in Mycobacterium tuberculosis . J Mol Model 21, 90 (2015). https://doi.org/10.1007/s00894-015-2630-4

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  • DOI: https://doi.org/10.1007/s00894-015-2630-4

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