title: Homology modeling, molecular dynamics and QM/MM study of the regulatory protein PhoP from Corynebacterium pseudotuberculosis.
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 (Mg(2+)) 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 Mg(2+) 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-Mg(2+) 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.
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Belém, PA, Brazil.
authors.forename: Gleiciane
authors.initials: G
authors.lastname: Moraes
authors.forename: Vasco
authors.initials: V
authors.lastname: Azevedo
authors.forename: Marcília
authors.initials: M
authors.lastname: Costa
authors.forename: Anderson
authors.initials: A
authors.lastname: Miyoshi
authors.forename: Artur
authors.initials: A
authors.lastname: Silva
authors.forename: Vivian
authors.initials: V
authors.lastname: da Silva
authors.forename: Diana
authors.initials: D
authors.lastname: de Oliveira
authors.forename: Maria Fátima
authors.initials: MF
authors.lastname: Teixeira
authors.forename: Jerônimo
authors.initials: J
authors.lastname: Lameira
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D016925:Corynebacterium pseudotuberculosis / Q000737:chemistry*; D008274:Magnesium; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory
chemical_list: D001426:Bacterial Proteins; C061064:PhoP protein, Bacteria; D008274:Magnesium