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Homology modeling, molecular dynamics and QM/MM study of the regulatory protein PhoP from Corynebacterium pseudotuberculosis

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Abstract

Corynebacterium pseudotuberculosis is a facultatively intracellular Gram-positive bacterium that causes caseous lymphadenitis, principally in sheep and goats, though sometimes in other species of animals, leading to considerable economic losses. This pathogen has a TCS known as PhoPR, which consists of a sensory histidine kinase protein (PhoR) and an intracellular response regulator protein (PhoP). This system is involved in the regulation of proteins present in various processes, including virulence. The regulation is activated by PhoP protein phosphorylation, an event that requires a magnesium (Mg2+) ion. Here we describe the 3D structure of the regulatory response protein (PhoP) of C. pseudotuberculosis through molecular modeling by homology. The model generated provides the first structural information on a full-length member of the OmpR/PhoP subfamily. Classical molecular dynamics was used to investigate the stability of the model. In addition, we used quantum mechanical/molecular mechanical techniques to perform (internal, potential) energy optimizations to determine the interaction energy between the Mg2+ ion and the structure of the PhoP protein. Analysis of the interaction energy residue by residue shows that Asp-16 and Asp-59 play an important role in the protein–Mg2+ ion interactions. These results may be useful for the future development of a new vaccine against tuberculosis based on genetic attenuation via a point mutation that results in the polar residue Asp-16 and/or Asp-59 being replaced with a nonpolar residue in the DNA-binding domain of PhoP of C. pseudotuberculosis.

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Acknowledgments

The authors would like to thank CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazilian Agencies) for their financial support of this work.

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Authors and Affiliations

  1. Laboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Belém, PA, Brazil

    Gleiciane Moraes, Jerônimo Lameira & Cláudio Nahum Alves

  2. Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil

    Gleiciane Moraes, Artur Silva & Jerônimo Lameira

  3. Laboratório de Genética Celular e Molecular, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

    Vasco Azevedo, Anderson Miyoshi & Vivian da Silva

  4. Núcleo de Genômica e Bioinformática, Universidade Estadual do Ceará, Fortaleza, CE, Brazil

    Marcília Costa, Diana de Oliveira & Maria Fátima Teixeira

Authors
  1. Gleiciane Moraes
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  2. Vasco Azevedo
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  3. Marcília Costa
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  4. Anderson Miyoshi
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  5. Artur Silva
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  6. Vivian da Silva
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  7. Diana de Oliveira
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  8. Maria Fátima Teixeira
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  9. Jerônimo Lameira
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  10. Cláudio Nahum Alves
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Corresponding author

Correspondence to Jerônimo Lameira.

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Moraes, G., Azevedo, V., Costa, M. et al. Homology modeling, molecular dynamics and QM/MM study of the regulatory protein PhoP from Corynebacterium pseudotuberculosis . J Mol Model 18, 1219–1227 (2012). https://doi.org/10.1007/s00894-011-1145-x

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  • DOI: https://doi.org/10.1007/s00894-011-1145-x

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