In Silico Analysis of Conformational Changes Induced by Normal and Mutation of Macrophage Infectivity Potentiator Catalytic Residues and its Interactions with Rapamycin.

The Legionella pneumophila (Lp), human pathogen, causes severe and often fatal Legionnaires' disease, produces a major virulence factor, termed 'macrophage infectivity potentiator protein' (Mip), that is necessary for optimal multiplication of the bacteria within human alveolar macrophages. Mip exhibits peptidyl prolyl cis-trans isomerase (PPIase) activity, which can be inhibited by rapamycin and FK506. It was previously shown that substitutions at the catalytic residues, aspartate-142 position replaced to leucine-142 and tyrosine-185 position replaced to alanine-185 strongly reduces the PPIase activity of Mip proteins. Therefore, we aim to develop an in silico mutagenesis model for both important catalytic residues, validated the stability of the mutated model. Further, we have docked the known inhibitor rapamycin with Lp Mip (native) and mutants (D142L and Y185A) to analyze the conformational and binding mode. Electrostatic contributions and van der Waals interactions are the major driving forces for rapamycin binding and largely responsible for the binding differences between the Lp Mip (native and mutated) proteins.