Computational exploration of novel antimicrobial modalities targeting fucose-binding lectins and ribosomes in Mycobacterium smegmatis using tRNA-encoded peptides.

tRNA-Encoded Peptides (tREPs), encoded by small open reading frames (smORFs) within tRNA genes, have recently emerged as a new class of functional peptides exhibiting antiparasitic activity. The discovery of tREPs has led to a re-evaluation of the role of tRNAs in biology and has expanded our understanding of the genetic code. This presents an immense, unexplored potential in the realm of tRNA-peptide interactions, paving the way for groundbreaking discoveries and innovative applications in various biological functions. This study explores the antimicrobial potential of tREPs against protein targets by employing a computational method that uses verified data sources and highly recognized predictive algorithms to provide a sorted list of likely antimicrobial peptides, which were then filtered for toxicity, cell permeability, allergenicity and half-life. These peptides were then docked with screened protein targets and computationally validated using molecular dynamics (MD) simulations for 150 ns and the binding free energy was estimated. The peptides Pep2 (VVLWRKPRVRKTG) and Pep6 (HRLRLRRRKPWW) exhibited good binding affinities of -110.5 +/- 2.5 and -129.0 +/- 3.9, respectively, with RMSD values of 0.4 and 0.25 nm against the fucose-binding lectin (7NEF) and the 30S ribosome of Mycobacterium smegmatis (5O5J) protein targets. The 7NEF-Pep2 and 5O5J-Pep6 complexes indicated higher negative binding free energies of -52.55 kcal/mol and -55.52 kcal/mol respectively, as calculated by Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA). Thus, the tREPs derived peptides designed as a part of this study, provide novel approaches for potential anti-bacterial therapeutic modalities.Communicated by Ramaswamy H. Sarma.

In silico investigations and molecular insights for designing tRNA-encoded peptides as potential therapeutics for targeting over-expressed receptors in breast cancer.

tRNA- Encoded Peptides (tREPs) have recently been discovered as new functional peptides and hold promise as therapeutics for anti-parasitic applications. In this study, in silico investigations were conducted to design tRNA-encoded peptides with the potential to target over-expressed receptors in breast cancer cells. tRNA genes were translated into corresponding peptides (tREPs) using computational tools. The tREPs, which were predicted as anticancer peptides, were then screened for various ADMET properties. Molecular docking studies were conducted for three cancer target receptors, the Estrogen Receptor (ER), Peroxisome Proliferator-Activated Receptor (PPAR) and the Epidermal Growth Factor Receptor (EGFR). Based on the docking results, specific tREPs were screened and molecular dynamics simulations were performed, and the binding energies were further explored using MMPBSA calculations. The peptide Pep1 (DWIAWRHHNDIVSWLTCGPRFKSWS) and Pep2 (GFIAWWSRHLELAQTRFKSWWS) exhibited a good binding affinity against the Estrogen Receptor (ER) and the Peroxisome Proliferator-Activated Receptor Alpha (PPAR) cancer target. The Pep1-ER and Pep1-PPAR complex maintained an average of two hydrogen bonds throughout the simulation and demonstrated a higher negative binding free energy of -72.27 kcal/mol and -65.16 kcal/mol respectively, as calculated by MMPBSA. Therefore, the tREPs designed as anticancer peptides in this study provide novel approaches for potential anticancer therapeutic modalities.Communicated by Ramaswamy H. Sarma.

Epigenetics, genomics imprinting and non-coding RNAs.

Epigenetic traits are heritable phenotypes caused by alterations in chromosomes rather than DNA sequences. The actual epigenetic expression of the somatic cells of a species is identical, however, they may show distinct subtleties in various cell types in which they may be affected. Several recent studies demonstrated that the epigenetic system plays a very important role in regulating all biological natural processes in the body from birth to death. We outline the essential elements of epigenetics, genomic imprinting, and non-coding RNAs in this mini-review.

In silico based multi-epitope vaccine design against norovirus.

Norovirus (NoV) belongs to the Calciviridae family that causes diarrhoea, vomiting, and stomach pain in people who have acute gastroenteritis (AGE). Identifying multi-epitope dependent vaccines for single stranded positive sense viruses such as NoV has been a long due. Although efforts have been in place to look into the candidate epitopes, understanding molecular mimicry and finding new epitopes for inducing immune responses against the T/B-cells which play an important role for the cell-mediated and humoral immunity was not dealt with in great detail. The current study focuses on identifying new epitopes from various databases that were filtered for antigenicity, allergenicity, and toxicity. The adjuvant ß-defensin along with different linkers were used for vaccine construction. Further, the binding relationship between the vaccine construct and toll-like immune receptor (TLR3) complex was determined using a molecular docking analysis, followed by molecular dynamics simulation of 100 ns. The vaccine candidate developed expresses good solubility with a score of 0.530, Z-score of -4.39 and molecular docking score of -140.4 ± 12.1. The MD trajectories reveal that there is a stability between TLR3 and the developed vaccine candidate with an average of 0.91 nm RMSD value and also the system highest occupancy H-bond formed between GLU127 of TLR3 and TYR10 of vaccine candidate (61.55%). Four more H-bonds exist with an occupancy of more than 32% between TLR3 and the vaccine candidates which makes it stable. Thus, the multi-epitope based vaccine developed in the present study forms the basis for further experimental investigations to develop a potentially good vaccine against NoV.Communicated by Ramaswamy H. Sarma.

Machine Learning Heuristics on Gingivobuccal Cancer Gene Datasets Reveals Key Candidate Attributes for Prognosis.

Delayed cancer detection is one of the common causes of poor prognosis in the case of many cancers, including cancers of the oral cavity. Despite the improvement and development of new and efficient gene therapy treatments, very little has been carried out to algorithmically assess the impedance of these carcinomas. In this work, from attributes or NCBI's oral cancer datasets, viz. (i) name, (ii) gene(s), (iii) protein change, (iv) condition(s), clinical significance (last reviewed). We sought to train the number of instances emerging from them. Further, we attempt to annotate viable attributes in oral cancer gene datasets for the identification of gingivobuccal cancer (GBC). We further apply supervised and unsupervised machine learning methods to the gene datasets, revealing key candidate attributes for GBC prognosis. Our work highlights the importance of automated identification of key genes responsible for GBC that could perhaps be easily replicated in other forms of oral cancer detection.

A Systems Model of Parkinson's Disease Using Biochemical Systems Theory.

Parkinson's disease (PD), a neurodegenerative disorder, affects millions of people and has gained attention because of its clinical roles affecting behaviors related to motor and nonmotor symptoms. Although studies on PD from various aspects are becoming popular, few rely on predictive systems modeling approaches. Using Biochemical Systems Theory (BST), this article attempts to model and characterize dopaminergic cell death and understand pathophysiology of progression of PD. PD pathways were modeled using stochastic differential equations incorporating law of mass action, and initial concentrations for the modeled proteins were obtained from literature. Simulations suggest that dopamine levels were reduced significantly due to an increase in dopaminergic quinones and 3,4-dihydroxyphenylacetaldehyde (DOPAL) relating to imbalances compared to control during PD progression. Associating to clinically observed PD-related cell death, simulations show abnormal parkin and reactive oxygen species levels with an increase in neurofibrillary tangles. While relating molecular mechanistic roles, the BST modeling helps predicting dopaminergic cell death processes involved in the progression of PD and provides a predictive understanding of neuronal dysfunction for translational neuroscience.