title: Molecular modeling studies of the interaction between Plasmodium falciparum HslU and HslV subunits.
abstract: The PfHslUV, a Plasmodium falciparum homolog of prokaryotic HslUV systems, is a newly identified drug target. The HslUV complex is an assembly of Heat Shock Locus gene products U and V. The formation of complete complex is essential for the proteasome to carry out its biochemical and physiological role in the parasite, namely to degrade specific target proteins in an ATP-dependent chaperone assisted manner. PfHslV subunit, a protease, exhibits increased proteolytic activity in the presence of PfHslU, the subunit believed to be responsible for allosteric activation of PfHslV. In the present work, we have employed computational methods to simulate the interaction of PfHslU and PfHslV subunits. We have used three methods--namely homology modeling, molecular docking and computational alanine scanning to model the complex, to predict the binding mode of PfHslU-V interaction and to predict the binding-energy hot-spots in protein-protein interface, respectively. The three dimensional models of PfHslV and PfHslU have been generated using MODELLER, based on the crystal structures of prokaryotic HslUV complex as templates. The modeled structures were docked using PatchDock, a geometry-based molecular docking algorithm. Finally, a three-dimensional PfHslUV complex model was generated that helped in comparing protein-protein interface characteristics with that of crystal structures of prokaryotic HslUV. Further, computational alanine scanning analysis of the generated complex was performed to calculate the binding free energy changes (DeltaDeltaGbind), which helped in identifying residues crucial for PfHslU and PfHslV interactions.
authors.affiliation: Structural and Computational Biology Group, International Center for Genetic Engineering and Biotechnology (ICGEB), New Delhi.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Asif
authors.initials: A
authors.lastname: Mohmmed
authors.forename: Dinesh
authors.initials: D
authors.lastname: Gupta
mesh_terms: D000595:Amino Acid Sequence; D006360:Heat-Shock Proteins / Q000737:chemistry*; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry; D015800:Protozoan Proteins / Q000737:chemistry*; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D006360:Heat-Shock Proteins; D021122:Protein Subunits; D015800:Protozoan Proteins; D046988:Proteasome Endopeptidase Complex