B.TEch Bioinformatics

Many systems in nature, including biological systems, have very complex dynamics which generate random-looking time series. Biological system dynamics is basically understood by physico-mathematical models which gives the basics of the atomic/molecular interaction in living nature. The moment of the object in universe either with respect to time or space is made under the physico- mathematics. To better understand a particular dynamical system, it is often of interest to determine whether the system is caused by static subsystem, deterministic subsystems stochastic subsystems, or all. Alternatively, one can use methods that measure the complexity in a particular system which seldom make assumptions about a particular system, such as assuming the presence of stationarity. Additionally, mathematical and computational modelling techniques can be used to test different hypothesis about the dynamics of biological systems.

The computer-aided drug design is an important tool in modern medicinal chemistry. Molecular lipophilicity usually quantified as log P and aqueous solubility usually defined as log S, are important molecular characteristics in medicinal chemistry and also in rationalized drug design. Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. The solubility, permeability, metabolic stability and protein binding need to be optimized simultaneously with potency, selectivity, and other biological parameters. The log P and log S coefficients are well-known as the principal parameters for the estimation of lipophilicity and solubility of chemical compounds and determine their pharmacokinetic properties.

Protein seldom performs biological activities in isolation. Understanding the protein-protein interactions' physical rewiring in response to pathological conditions or pathogen infection can help advance our comprehension of disease etiology, progression, and pathogenesis, which allow us to explore the alternate route to control the regulation of key target interactions, timely and effectively. Nonalcoholic steatohepatitis (NASH) is now a global public health problem exacerbated due to the lack of appropriate treatments. The most advanced anti-NASH lead compound (selonsertib) is withdrawn, though it is able to inhibit its target Apoptosis signal-regulating kinase 1 (ASK1) completely, indicating the necessity to explore alternate routes rather than complete inhibition. Understanding the interaction fingerprints of endogenous regulators at the molecular level that underpin disease formation and progression may spur the rationale of designing therapeutic strategies. Based on our analysis and thorough literature survey of the various key regulators and PTMs, the current review emphasizes PPI-based drug discovery's relevance for NASH conditions. The lack of structural detail (interface sites) of ASK1 and its regulators makes it challenging to characterize the PPI interfaces. This review summarizes key regulators interaction fingerprinting of ASK1, which can be explored further to restore the homeostasis from its hyperactive states for therapeutics intervention against NASH.

Mutations in homodimeric isocitrate dehydrogenase (IDH) enzymes at specific arginine residues result in the abnormal activity to overproduce D-2 hydroxyglutarate (D-2HG), which is often projected as solid oncometabolite in cancers and other disorders. As a result, depicting the potential inhibitor for D-2HG formation in mutant IDH enzymes is a challenging task in cancer research. The mutation in the cytosolic IDH1 enzyme at R132H, especially, may be associated with higher frequency of all types of cancers. So, the present work specifically focuses on the design and screening of allosteric site binders to the cytosolic mutant IDH1 enzyme. The 62 reported drug molecules were screened along with biological activity to identify the small molecular inhibitors using computer-aided drug design strategies. The designed molecules proposed in this work show better binding affinity, biological activity, bioavailability, and potency toward the inhibition of D-2HG formation compare to the report...

Multiple processes exist in a cell to ensure continuous production of essential proteins either through cap-dependent or cap-independent translation processes. Viruses depend on the host translation machinery for viral protein synthesis. Therefore, viruses have evolved clever strategies to utilize the host translation machinery. Earlier studies have shown that genotype 1-Hepatitis E virus (g1-HEV) utilizes both cap-dependent and cap-independent translation machineries for its replication and proliferation. Cap-independent translation in g1-HEV is driven by an eighty seven nucleotide-long RNA element which acts as a noncanonical, internal ribosome entry site like (IRESl) element. Here, we have identified the RNA-protein interactome of the HEV IRESl element and characterized the functional significance of some of its components. Our study reveals indispensable roles of host ribosomal protein RPL5 and DHX9 (RNA helicase A) in mediating efficient translation from the IRESl element and e...

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights  Significance of three highly conserved mutations of GJB1 gene at position 75  Investigated using MD simulation analysis  The three mutants displayed a lesser protein stability with respect to native.  Mutants alter the hydrophobicity and hydrophilicity balance of ion channel.

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The COVID-19 pandemic caused by SARS-CoV-2 has a significant burden on the economy and healthcare around the world. Vaccines are the most effective tools to fight infectious diseases by containing the spread of the disease. The current vaccines against SARS-CoV-2 are mostly based on the spike protein of SARS-CoV-2, which is large and has many immune-dominant non-neutralizing epitopes that may effectively skew the antibody response towards non-neutralizing antibodies. Here, we have explored the possibility of immune-focusing the receptor binding motif (RBM) of the spike protein of SARS-CoV-2 that induces mostly neutralizing antibodies in natural infection or in vacinees. The result shows that the scaffolded RBM can bind to Angiotensin Converting Enzyme 2 (ACE2) although with low affinity and induces a strong antibody response in mice. The immunized sera can bind both, the receptor binding domain (RBD) and the spike protein, which holds the RBM in its natural context. Sera from the immunized mice showed robust interferon γ response but poor neutralization of SARS-CoV-2 suggesting presence of a predominant T cell epitope on scaffolded RBM. Together, we provide a strategy for inducing strong antigenic T cell response which could be exploited further for future vaccine designing and development against SARS-CoV-2 infection.

The NF1 gene encodes for neurofibromin protein, which is ubiquitously expressed, but most highly in the central nervous system. Non-synonymous SNPs (nsSNPs) in the NF1 gene were found to be associated with Neurofibromatosis Type 1 disease, which is characterized by the growth of tumors along nerves in the skin, brain, and other parts of the body. In this study, we used several in silico predictions tools to analyze 16 nsSNPs in the RAS-GAP domain of neurofibromin, the K1444N (K1423N) mutation was predicted as the most pathogenic. The comparative molecular dynamic simulation (MDS; 50 ns) between the wild type and the K1444N (K1423N) mutant suggested a significant change in the electrostatic potential. In addition, the RMSD, RMSF, Rg, hydrogen bonds, and PCA analysis confirmed the loss of flexibility and increase in compactness of the mutant protein. Further, SASA analysis revealed exchange between hydrophobic and hydrophilic residues from the core of the RAS-GAP domain to the surface of the mutant domain, consistent with the secondary structure analysis that showed significant alteration in the mutant protein conformation. Our data concludes that the K1444N (K1423N) mutant lead to increasing the rigidity and compactness of the protein. This study provides evidence of the benefits of the computational tools in predicting the pathogenicity of genetic mutations and suggests the application of MDS and different in silico prediction tools for variant assessment and classification in genetic clinics.

Nonalcoholic steatohepatitis (NASH) is a global health concern with no effective treatment options. Apoptosis-signaling kinase 1 (ASK1) hyperactivity induced by oxidative stress has been identi ed as a key contributor to hepatic in ammation, apoptosis, and liver brogenesis, is the hallmark of NASH. Several attempts by companies and academia have attempted to develop ASK1 inhibitors, however, they failed in clinical trials due to substantial side effects. Hence, there is an unmet need for an alternate approach such as protein-protein interactions (PPIs) to modulate ASK1 activity via allosteric regulators rather than complete blockage of ASK1. The PPI driven allosteric inhibition of ASK1 traverses a promising strategy as its regulators in disease states are well documented. Among them, 14-3-3, a-ve regulator that allosterically inhibits ASK1 as it restricts the access of the catalytic site by preventing the substrate from entering into the catalytic site, however the mechanistic insights have not been explored. The 14-3-3 binding site and its impact at catalysis site is wired through an unstructured region indicating the possibility that this process is highly dynamics coupled, a major bottleneck in PPI-based inhibitor designing. Therefore, we are investigating the structural behavior of 14-3-3 and ASK1 interfaces using molecular modeling and microsecond molecular dynamics simulations. We identi ed that dynamics which correlate the structural and functional implications of the allosteric modulation via 14-3-3 on ASK1's catalytic site and underscores a novel strategy for allosteric inhibition of ASK1. Extensive molecular dynamics simulations revealed that the complex state of ASK1 (with 14-3-3) was more stable than the apo state with a more restricted catalytic pocket volume as it visualizes that it potentially prevents the substrate entry in the absence of a ligand. Our ndings provide structural determinants of allosteric regulation of ASK1 by 14-3-3 for the development of novel therapeutics against ASK1.