A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis.

Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57 kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and - 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder.

Transcriptomic analysis reveals zinc-mediated virulence and pathogenicity in multidrug-resistant Acinetobacter baumannii.

Acinetobacter baumannii is a gram-negative bacterium well known for its multidrug resistance and connection to nosocomial infections under ESKAPE pathogens. This opportunistic pathogen is ubiquitously associated with nosocomial infections, posing significant threats within healthcare environments. Its critical clinical symptoms, namely, meningitis, urinary tract infections, bloodstream infections, ventilator-associated pneumonia, and pneumonia, catalyze the imperative demand for innovative therapeutic interventions. The proposed research focuses on delineating the role of Zinc, a crucial metallo-binding protein and micronutrient integral to bacterial metabolism and virulence, to enhance understanding of the pathogenicity of A. baumannii. RNA sequencing and subsequent DESeq2 analytical methods were used to identify differential gene expressions influenced by zinc exposure. Exploiting the STRING database for functional enrichment analysis has demonstrated the complex molecular mechanisms underlying the enhancement of pathogenicity prompted by Zinc. Moreover, hub genes like gltB, ribD, AIL77834.1, sdhB, nuoI, acsA_1, acoC, accA, accD were predicted using the cytohubba tool in Cytoscape. This investigation underscores the pivotal role of Zinc in the virulence of A. baumannii elucidates the underlying molecular pathways responsible for its pathogenicity. The research further accentuates the need for innovative therapeutic strategies to combat A. baumannii infections, particularly those induced by multidrug-resistant strains.

Elucidating the mutational impact in causing Niemann-Pick disease type C: an in silico approach.

Niemann-Pick disease type C is a rare autosomal recessive of lysosomal storage disorder characterized by impaired intracellular lipid transport and has a tendency to accumulate the fatty acids and glycosphingolipids in a variety of neurovisceral tissues. This work includes computational tools to deciphere the mutational effect in NPC protein. The study initiated with the collection of 471 missense mutations from various databases, which were then analyzed using computational tools. The mutations (G549V, F703S, Q775P and L1244P) were said to be disease associated, altering the biophysical properties, in highly conserved regions and reduces the stability using several in silico methods and were subjected to molecular docking analysis. To analyze the ligand (Itraconazole: a small molecule of antifungal drug class, which is known to inhibit cholesterol export from lysosomes) activity Molecular docking study was performed for all the complex proteins. The average binding affinity was taken and found to be -10.76 kcal/mol (native) and -11.06 kcal/mol (Q775P was located in transmembrane region IV which impacts the sterol-sensing domain of the NPC1 protein and associated with a severe infantile neurological form). Finally, molecular dynamic simulation was performed in duplicate and trajectories were built for the backbone of the RMSD, RMSF, the number of intramolecular hydrogen bonds, the radius of gyration and the SSE percent for both the complex proteins. This work contributes to understand the effectiveness and may provide an insight on the stability of the drug with the complex variant structures.Communicated by Ramaswamy H. Sarma.

Unravelling the Relacatib activity against the CTSK proteins causing pycnodysostosis: a molecular docking and dynamics approach.

Pycnodysostosis is an atypical autosomal recessive condition of Lysosomal storage disorder that originated due to the deficit of the enzyme Cathepsin K which is vital for normal osteoclast action in bone resorption. Abnormal degradation of type 1 collagen and accumulation of toxic undigested collagen fibers in lysosomes of the osteoclast cells resulting in high bone density, brittle bones, and a short stature is caused in CTSK protein-carrying individuals. The broad aim of this study is to identify the most significant variant through various computational pipelines. This study was initiated by retrieving a total number of thirty-six variants from NCBI, HGMD, and UniProt databases, and the Y283C variant was found to be more significant by various standard computational tools. A structural investigation was performed to understand and gain a better knowledge about the interaction profile for the native (1BY8) and variant (Y283C) with Relacatib (a small-molecule drug that blocks the function of Cathepsin K, an enzyme that has been linked to osteoporosis, osteoarthritis, and other bone-degrading diseases). The interaction profile was analyzed using molecular docking. Relacatib (ligand) had an average binding affinity for both native (-7.16 kcal/mol) and Y283C (-6.76 kcal/mol). Finally, Molecular dynamics simulations were done in duplicates to recognize the variant (Y283C) activity of the protein structure against Relacatib for 100 ns. This study assists in comprehending the most pathogenic amino-acid variant, the ligand interaction with the protein structure, and paves the way for understanding the steadiness of the ligand with the native and selected significant amino-acid variant.Communicated by Ramaswamy H. Sarma.