An integrative approach using systems biology, mutational analysis with molecular dynamics simulation to challenge the functionality of a target protein

Abstract

Visceral leishmaniasis affects millions of people worldwide in areas where Leishmania donovani is endemic. The protozoan species serves a greater threat as it has gradually evolved drug resistance whereby requiring newer approaches to treat the infection. State‐of‐art techniques are mostly directed toward finding better targets extracted from the available proteome data. In light of recent computational advancements, we ascertain and validate one such target, adenylosuccinate lyase (ADSL) by implementation of in‐silico methods which led to the identification of critical amino acid residues that affects its functional attributes. Our target selection was based on comprehensive topological analysis of a knowledge‐based protein–protein interaction network. Subsequently, mutations were incorporated and the dynamic behavior of mutated and native proteins was traced using MD simulations for a total time span of 600 ns. Comparative analysis of the native and mutated structures exhibited perceptible changes in the ligand‐bound catalytic region with respect to time. The unfavorable changes in the orientations of specific catalytic residues, His118 and His196, induced by generated mutations reduce the enzyme specificity. In summary, this integrative approach is able to select a target against pathogen, identify crucial residues, and challenge its functionality through the selected mutations.

Computational Analysis of the Silver Nanoparticle–Human Serum Albumin Complex

“…To comprehend the functionality and dynamics of the protein and protein–ligand systems, MDS has been extensively utilized. − Therefore, in order to understand the dynamic behavior of the protein in the presence of NPs, molecular dynamics simulations were carried out with the GROMACS (Groningen Machine for Chemical Simulations) 2016.4 version. , The parameterized GROMOS 54A7 force field was utilized for all of the simulations. In this study, seven sets of simulations were carried out, that is, that of only the HSA protein and of the AgNP and five sets of protein–NP conjugate systems.…”

Perspectives From Systems Biology to Improve Knowledge of Leishmania Drug Resistance

“…Systems biology is interdisciplinary and includes a wide range of data from in vivo, in vitro, in situ, and in silico studies. Ideally, in silico studies would be integrated and validated by other data sources especially when applicable outcomes are aimed (Butcher et al, 2004;Dunn et al, 2010;Bora and Jha, 2019).…”

Role of Force Fields in Protein Function Prediction

“…With the advancement of both experimental and computational techniques, availability of 3D data in regard to proteins, proteins complexes, membrane proteins etc. has been possible which made the system size amplified to several lakhs of atoms with explicit solvent in consideration [50]. Meanwhile the advent of high-performance computing (HPC) and algorithm parallelization made it possible to run long timescale simulations for the above-mentioned systems.…”