Biology subjects

Jabeen, I.

Publications and source records attributed to Jabeen, I..

3 recordsLinked to original sources

bioRxiv2026

Downstream mRNA Secondary Structure, Not Codon Elongation Supply, Coordinates Co-Translational Protein Folding Across the Human Ribosomal Exit Tunnel

How ribosomes pace translation to assist nascent protein folding remains an open question in molecular biology. While synonymous codon selection is widely hypothesized to regulate elongation rates to facilitate domain organization, distinguishing genuine translational kinetics from baseline amino acid preferences has proven technically difficult. Here, we analyze a non-redundant cohort of 1,270 high-resolution human crystal structures (410,151 residues) mapped to their native mRNA transcripts. When we mathematically isolate synonymous codon choices from amino acid identity using orthogonal linear projection, standard codon-supply metrics i.e. the tRNA Adaptation Index (tAI) and the Codon Adaptation Index (CAI), show negligible independent spatial coupling with downstream protein structure. Their uncorrected correlations predominantly reflect local amino acid chemistry rather than physical translation pacing. In contrast, downstream mRNA secondary structure stability (minimum free energy, MFE) displays a subtle but consistent correlation that survives amino acid control. Across 100,000 whole-proteome permutations per pair, this MFE signal centers at an offset of +15 to +16 codons across multiple independent physical properties, including residue packing density (r = -0.0699, Z = -23.64, p < 10-5), crystallographic rigidity (B-factor, r = +0.0614, Z = +13.74, p < 10-5), and solvent burial (SASA, r = +0.0492, Z = +18.98, p < 10-5). This +15 codon offset corresponds directly to the physical dimensions of the eukaryotic 80S ribosome: the path from the peptidyl transferase center to the internal uL4/uL22 constriction neck (~10 amino acids) plus the downstream mRNA helicase entry channel (~5 codons). While the overall effect size is modest, accounting for approximately 0.49% of local packing variance, its spatial specificity and consistency across independent structural metrics suggest that downstream mRNA stability acts as a localized mechanical brake during early chain compaction.

bioinformatics↗

bioRxiv2025

Integrative metagenomics and structural bioinformatics identify explainable gut microbial variants associated with Crohns disease

Metagenomics has revealed disease-associated shifts in microbial taxa and functions in inflammatory bowel disease (IBD) patients. However, the role of genomic variation in gut commensals remains poorly understood. Here, we integrated metagenomic profiling, variant calling, and structural bioinformatics to identify disease-associated variants in the gut microbes. Crohns disease (CD) and ulcerative colitis (UC) showed significant negative associations with Bacteroides uniformis, Bacteroides vulgatus, and Eubacterium rectale. These bacteria exhibited 190,712 single-nucleotide polymorphisms, including 479 CD-specific and 235 UC-specific variants. Variant prioritization identified a CD-specific Val170Leu substitution in the conserved starch-binding domain of the Starch Utilization System D (SusD) protein in B. uniformis. Structural modeling and cyclodextrin docking indicated reduced binding affinity in the mutant, while 200-ns molecular dynamics simulations showed stable ligand retention only in the wild type. These findings suggest that impaired starch metabolism driven by SusD variation may contribute to B. uniformis depletion in CD and demonstrate the value of integrating metagenomics with structural analyses to identify functionally relevant microbial variants.

bioinformatics↗

bioRxiv2025

Conservation of the hydrogen-bond network in bacterial response regulators

The bacterial response regulator (RR) superfamily is activated by single aspartyl phosphorylation to modulate a distant target binding surface for diverse functions. The enteric CheY RRs, which represent the chemotaxis subfamily, have been extensively characterized. Their native, chemical or genetically-altered crystal structures have revealed an essential role for water-mediated hydrogen bonds (H-bonds) in activation. Here, we use molecular dynamics (MD) to compare the protein-water H-bond network in basal and in-silico phosphorylated conformations. We supplement the MD with energy frustration profiles for atomic structures and models from selected RR superfamily representatives. The energetically frustrated phosphorylation pocket consists of the conserved aspartate triad for phosphorylation, plus associated structural waters and residues for Mg2+ ion coordination. It orchestrates the H-bond network characterized here in atomic detail. The network has an energetically stable core. Its plastic nodes switch bonding states coupled to loop flexibility and sidechain rotations. Mutual information revealsthat the long-range, dynamic networks respond to single H-bond transitions. The network centrality of the phosphorylation pocket, connected to the target binding surface by water-mediated channels via the conserved switch residues (T87, K109), increases upon phosphorylation. Analysis of other RR representatives suggests this design is a generic feature of RR allostery with subtle, function-dependent differences. The water contribution may prove critical for the design of specific RR sub-family specific, allosteric inhibitors.

biophysics↗