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

Abstract

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.

In Silico Analyses, Experimental Verification and Application in DNA Vaccines of Ebolavirus GP-Derived pan-MHC-II-Restricted Epitopes

“…Molecular docking has been recognized as a valuable technique in computer-aided vaccine design [40,41]. The docking between 19 cross-species reactive epitopes and HLA-II molecules was simulated, suggesting that the affinity prediction results and the molecular docking calculation can be mutually validated.…”

Structure-based inhibitor screening of natural products against NSP15 of SARS-CoV-2 revealed thymopentin and oleuropein as potent inhibitors

“…Docking studies [30][31][32][33][34] were performed using GOLD [35], and the protein was kept as a rigid molecule, and the number of Genetic Algorithm (GA) runs was set to 10 runs per ligand with the default search algorithm parameters. GOLD score was then used as the final scoring method.…”

Pharmacophore based virtual screening for identification of marine bioactive compounds as inhibitors against macrophage infectivity potentiator (Mip) protein of Chlamydia trachomatis

“…In this mutational study, the sequence of C. trachomatis Mip (native) at the 170 th position ASP was replaced by LEU and at the 213 th position TYR was replaced by ALA to predict protein stability changes using the I-mutant server. 15 Loss of stability by the mutant protein with negative Gibbs free energy values of À1.70 and À1.52 at pH 7.0 and 37 C were observed (Table 1) (http://gpcr.biocomp.unibo.it/cgi/predictors/I-Mutant 2.0/I-Mutant 2.0.cgi).…”

“…Also mutation of the Legionella pneumophila Mip protein on catalytic residues at the aspartate-142 position replaced by leucine-142 and the tyrosine-185 position replaced by alanine-185 strongly reduces PPIase activity. 13 In order to design a drug for treating chlamydial infections, we constructed an in silico mutagenesis 14,15 model for both important catalytic residues (aspartate-170 to leucine-170 and tyrosine-213 to alanine-213) of C. trachomatis Mip, 16 validated the stability of the mutated model. The Universal Natural Products Database (UNPD) 17 was created to be a comprehensive resource of natural products for virtual screening.…”