Biology subjects

Uversky, V. N.

Publications and source records attributed to Uversky, V. N..

At least 19 recordsLinked to original sources

bioRxiv2026

Predicted condensation-related signatures localize to two C-terminal regions of the prion protein across cervid PRNP variants associated with chronic wasting disease

Genetic variation in cervid PRNP influences chronic wasting disease (CWD) susceptibility and progression, but it remains unclear whether disease-associated substitutions produce localized differences in sequence-derived properties relevant to prion protein (PrPC) condensation. We compared a white-tailed deer (WTD) reference sequence with 10 modeled variants on the same mature PrP scaffold (residues 24-233). For each sequence, we calculated intrinsic disorder, FuzDrop per-residue droplet-promoting propensity (pDP) and binding-mode entropy (Sbind), predicted residue-level pKa values, and a discrete-charge summary at pH 7.0. The overall profiles preserve a long N-terminal droplet-promoting region, whereas variant-associated differences are concentrated in selected intervals. In the FuzDrop outputs, residues 126-140 show allele-dependent changes in pDP near the droplet-promoting threshold, and residues 220-230 show variant-specific changes in Sbind, including lower Sbind for S225F/Y and higher Sbind for elk-like Q226E. These differences occur without large changes in overall intrinsic disorder. KaML pKa predictions identify near-neutral titratable sites that provide electrostatic context for these local predictor differences. Independent atomistic simulations of monomeric PrP further detected variant-sensitive backbone behavior and intramolecular contacts involving these intervals. Together, the analysis identifies residues 126-140 and 220-230 as computationally defined candidate intervals that overlap regions implicated independently in prion conversion or CWD fibril structure, motivating direct tests of cervid PrP condensation and maturation.

bioinformatics↗

bioRxiv2026

Mathematical genomics of SRY proteins and their associated HMG-Box domains across mammals

Male sex determination in mammals depends on sex-determining region Y (SRY), a transcription factor whose high-mobility group box (HMG box) binds and bends DNA to activate SOX9. The divergent N- and C-terminal domains lack sequence homology and have been dismissed as passive linkers, yet alignment-based homology cannot reveal whether they retain a hidden compositional grammar. We applied quantitative genomics to 65 full-length mammalian SRY proteins and 38 HMG-box subsequences across 75 mammals, integrating amino acid and dipeptide compositions, Shannon entropy, dominant-residue profiles, hydropathy-based n-gram spectra, longest hydropathy stretches, and cumulative proximity. The HMG box is tightly constrained: basic residues dominated, cysteine was nearly absent, entropy clustered near 4.0, polar content averaged 58.44\%, and 25 of 38 HMG boxes shared 57.97\% polar residues, whereas full-length SRY varied more, with rodents showing high polar and glutamine-rich profiles and cetaceans low polar content. Proximity-based clustering was more taxonomically consistent at the HMG level, while terminal regions blurred domain-level signals. Across 65 SRY proteins and 38 HMG domains, intrinsic disorder was the dominant predicted state, and a polyQ-rich rodent SRY illustrated how low-complexity repeats can produce misleading ordered predictions, underscoring the need for consensus disorder analysis in rapidly evolving intrinsically disordered regions. Cumulative proximity analysis identified \textit{Bos taurus} and \textit{Bos grunniens} as the only pair proximally clustered at both the full-length SRY and SRY-HMG levels, establishing multivariate proximity as a stringent criterion of compositional similarity satisfied by a single mammalian pair. These results suggest that SRY and its HMG box each carry a distinct compositional grammar, quantifiable only through alignment-independent signatures, with compositional individuality being the rule rather than the exception. These quantitative signatures provide a framework for interpreting SRY variation, assessing clinical mutations, and understanding evolutionary pressures shaping sex determination. Denser taxon sampling, structural modeling, and experimental tests are needed to clarify whether HMG-box drift and terminal-region variation affect DNA binding, bending, or reproductive function.

bioinformatics↗

bioRxiv2026

Charged residues, not aromatics, are the universal topological hubs of intrinsically disordered proteins

The stickers and spacers model assigns aromatic residues as the primary drivers of IDP phase separation predicting that aromatics also occupy topologically central hub positions in IDP contact networks. Analysing a proteome wide simulation dataset spanning six taxa we find that charged residues not aromatics are the universal network hubs with glutamate the strongest hub in every taxon and aromatics predominantly anti hub. All IDP contact networks are universally positively assortative a sequence encoded topological law in which hub identity is positionally encoded. That hub character requires charge carrier geometry rather than charge alone is demonstrated by a natural experiment in which arginine and lysine carry identical net charge yet arginine is a universal hub while lysine is a near neutral spacer (Cohens d = 2.456) confirmed by force field cross validation and wet lab condensate miscibility data. Charge matched synuclein K[->]R slab simulations reveal that hub character governs condensate density and thermodynamic stability without altering the nucleation threshold connecting single chain topology to multi chain phase thermodynamics. Tyrosine hub character tracks the prokaryote eukaryote boundary with evolutionary encoding the only explanation to survive direct testing. Together these results establish hub identity and sticker identity as complementary organisational principles of disordered sequences governed by distinct residue chemistries and shaped independently by selection.

biophysics↗

bioRxiv2026

Quantitative Deciphering of Mammalian Histamine Receptors through Mathematical Genomics

Histamine receptors (HRH1-HRH4) are G-protein coupled receptors (GPCRs) that mediate essential physiological functions, including neurotransmission, gastric acid secretion, immune regulation, and presynaptic autoregulation. Despite their importance, systematic comparative analyses across mammalian histamine receptor sequences remain scarce. In this study, we performed a comprehensive evaluation of HRH1-HRH4 across multiple mammalian species, integrating sequence homology, invariant residue mapping, amino acid substitutions, compositional frequencies, Shannon entropy, polystring distributions, intrinsic disorder profiling, and phylogenetic clustering. HRH2 and HRH1 were highly conserved among primates, HRH3 showed strong cohesion within rodents, while HRH4 exhibited pronounced divergence consistent with immune-related specialization. Invariant residues localized to transmembrane helices and activation motifs (D107, W428/Y431, NPxxY), underscoring strict evolutionary constraints on ligand binding, receptor stability, and G-protein coupling. Substitutions were confined to non-essential lipid-facing and loop regions, predominantly conservative in nature, enabling diversification without disrupting the GPCR fold. Amino acid frequency and entropy analyses revealed hydrophobic dominance with subtype-specific enrichment of polar residues, while disorder profiling identified HRH1 as the most dynamic and HRH2 as the most structurally constrained. Polystring analysis highlighted conserved motifs (WWW, PP) alongside subtype- and species-specific repeats, reflecting evolutionary strategies balancing receptor stability with adaptive flexibility. Phylogenetic clustering confirmed subtype-specific cohesion, with HRH3 and HRH4 forming compact clades, HRH1 showing moderate dispersion, and HRH2 forming the most isolated cluster. Collectively, these findings demonstrate that mammalian histamine receptor evolution is governed by conserved biophysical cores and selective variability, offering insights into structural conservation, functional diversification, and translational relevance for drug design and model selection.

bioinformatics↗

bioRxiv2026

Network of Interactions between the Tumor Necrosis Factor Superfamily Members and Small S100 Proteins

Tumor Necrosis Factor Superfamily (TNFSF) comprises 20 members of membrane/soluble signaling proteins regulating cell survival, cell proliferation/differentiation, and innate/adaptive immunity. Targeting signaling of TNFSF members is used clinically to treat several autoimmune and oncological diseases, and bone loss. They and their cognate receptors are in clinical trials as targets for treatment of autoimmune, inflammatory, oncological and other diseases. Recently, some representatives of S100 family of pleiotropic calcium-binding proteins were shown to interact with TNFSF members TNF and TRAIL, thereby suppressing their activity. In this work, we explored selectivity of interactions between soluble forms of 13 TNFSF members and 21 non-fused S100 proteins using surface plasmon resonance spectroscopy. A total of 27 interactions were found between CD70, CD30L, 4-1BBL, TWEAK, APRIL, LIGHT, VEGI and AITRL and Ca2+-loaded forms of S100A1/A2/A4/A5/A6/A12/A16/B/P proteins, with equilibrium dissociation constants from 2 nM to 24 M. Removal of calcium leads to disruption of the interactions. Molecular docking indicates presence of well-conserved binding sites of the both interaction partners. Mutagenesis of S100P evidences involvement of its hinge region in binding of CD30L, VEGI and AITRL, as well as F89 residue in VEGI recognition. The revealed network of interactions is potentially important for regulation of the cellular communication mediated by TNFSF/S100 proteins, which could be exploited for targeted therapy of socially significant diseases.

biophysics↗

bioRxiv2026

Adaptive Landscapes of Plasmodium Falciparum Dihydrofolate Reductase Reveal Pathways to Antifolate Resistance

Antifolate resistance in Plasmodium falciparum dihydrofolate reductase (pfDHFR) remains a major challenge for malaria control. To understand how this enzyme maintains function under antifolate selection, we developed PfPATH, a computational framework that integrates mutational fitness measurements, evolutionary interactions, and structural information to map adaptive trajectories. PfPATH adaptive walks reveal that evolution is constrained to a narrow ridge in sequence space defined by a small subset of residues. Most resistance mutations are individually deleterious and become viable only when supported by stabilizing changes, restricting adaptation to a few high-resistance pathways. Structure network analyses show that these mutations do not disrupt the global enzyme architecture but instead reorganize internal communication to preserve catalytic function. Consistent with this, molecular dynamics and free-energy analyses indicate that resistant variants remain stable while sampling a broader ensemble of low-energy conformational substates. Together, these results reveal a narrow and predictable route to antifolate escape.

biophysics↗

bioRxiv2025

AlphaFold3 and Intrinsically Disordered Proteins: Reliable Monomer Prediction, Unpredictable Multimer Performance

AlphaFold3 represents a major advance in protein structure prediction, yet its performance on intrinsically disordered proteins remains uncharacterized. We present the first systematic evaluation of AF3 on disordered systems, revealing a striking dichotomy. For monomers, AF3s pLDDT scores reliably predict disorder (MCC: 0.693), matching AlphaFold2 and rivaling dedicated predictors. This consistency across fundamentally different architectures confirms that disorder prediction emerges from training data, not model design. For multimers, the picture grows complex. Despite comparable aggregate performance (mean DockQ: 0.563 vs 0.571), AF3 and AF2 achieve these results through fundamentally different mechanisms. Conventional structural features explain 58% of AF2s variance but only 42% of AF3s. Users cannot predict when AF3 will succeed or fail from interface properties alone. On disorder-to-order transitions (MFIB benchmark), both models perform equally well, successfully predicting final folded states. Yet seed variance analysis reveals AF3s failures are deterministic: the model converges to identical structures across independent runs, whether correct or incorrect, indicating rigid structural priors override available information. Our findings establish AF3 as reliable for the prediction of monomer disorder but unpredictable for multimers. Architectural innovation alone cannot overcome training data bias. Progress demands disorder-enriched datasets and ensemble sampling, not merely novel architectures.

bioinformatics↗

bioRxiv2025

CpG-induced regions associated compositional stratification of human essential proteins through mathematical genomics

CpG islands are genomic regions enriched in cytosine-phosphate-guanine dinucleotides, typically associated with gene promoters and regulatory elements. While their role in transcriptional regulation is well established, their influence on protein sequence composition remains underexplored. In this study, 3,222 essential proteins from Homo sapiens were analyzed to investigate the impact of CpG island architecture on amino acid usage, sequence complexity, and chromosomal distribution. Codons containing both cytosine and guanine were mapped to five CpG-induced amino acids, and their relative abundance was quantified across proteins. CpG-induced regions were identified using a sliding window approach, and metrics such as average CpG density, longest CpG-induced region length, and sequence coverage were computed. Motif composition within these regions was characterized using polarity and charge-based indices. Clustering revealed consistent bipartite subgroup structures, indicating compositional stratification among essential proteins. Shannon entropy quantified compositional complexity, revealing a significant shift between clusters (p = 5. x 50 10-145). Cluster 1 proteins showed lower entropy and greater heterogeneity, whereas Cluster 2 showed higher entropy and tighter distributions, indicating distinct regimes of variability. Additionally, we examined CpG island overlap within coding exons of essential genes and found that CpG-depleted proteins are predominantly encoded by genes with minimal CGI coverage, whereas CpG-induced proteins span both low- and high-overlap classes. CGI-associated CpGs were consistently enriched toward the 5' end of essential genes, indicating a positional bias in CpG distribution. These findings establish a quantitative framework linking CpG island distribution to proteomic architecture and offer a scalable strategy for motif annotation, epigenetic modeling, and functional stratification. Future applications include predictive modeling of protein function, disease association, and regulatory dynamics.

genomics↗

bioRxiv2025

A Mathematical Genomics Perspective on the Moonlighting Role of Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH)

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a well-conserved enzyme across Archaea, Bacteria, and Eukarya, known not only for its canonical role in glycolysis, but also for diverse moonlighting functions including transcription regulation, host-pathogen interactions, and immune modulation. Studying GAPDH quantitatively is crucial for understanding how subtle variations at the sequence and structural levels drive such functional diversity across evolutionary lineages. In this study, 165 GAPDH protein sequences from 158 organisms were analyzed to uncover conserved and divergent features underlying multifunctionality. While core catalytic residues were strongly preserved, selective enrichment of small non-polar residues such as valine and alanine suggested a structural basis for flexibility and adaptive potential. The balanced distribution of order- and disorder-promoting residues and the avoidance of long homopolymeric stretches indicated evolutionary selection for both structural coherence and local flexibility. Spatial distribution of amino acids in GAPDH sequences revealed low fractal variance across sequences, with moderate differences in residue clustering patterns pointing to localized adaptations without compromising overall organization. These findings demonstrate that GAPDH multifunctionality is encoded through compositional signatures and conserved spatial architecture, allowing the coexistence of metabolic stability and regulatory plasticity. The results have broad implications for understanding protein evolution, structural adaptability in extreme environments, and functional versatility in pathogenic contexts. This study establishes GAPDH as a model for exploring principles of protein moonlighting and highlights the potential of quantitative compositional analysis in uncovering hidden functional layers.

genomics↗

bioRxiv2025

CDKN1A (p21Cip/Waf1) stabilizes Cyclin D3 by inhibiting its phosphorylation-dependent nuclear export following butyrate treatment

Butyrate-mediated inhibition of cell proliferation is part of the preventive role of dietary fiber against colorectal cancer (CRC). This effect notably involves the cyclin-dependent kinase inhibitor CDKN1A (p21Cip/Waf1) in human intestinal cells, yet the underlying molecular mechanisms remain incompletely understood. Previously, we observed a paradoxical increase in cyclin D3 (CCND3)--but not cyclin D1--levels upon butyrate exposure. Here, we demonstrate that the butyrate-induced accumulation of CCND3 protein results both from mRNA increase and a CDKN1A-dependent protein stabilization, specifically extending its nuclear half-life. Proteomic analyses of CCND3 co-immunoprecipitates identified complexes involving CDKN1A, CDK4, CDK6, and the CRC-associated kinase CDK5, particularly enriched in butyrate-treated cells. Phosphorylation at a conserved Thr residue, crucial for CCND nuclear export and subsequent proteasomal degradation, was notably reduced following butyrate treatment and inversely correlated with CDKN1A expression levels. Structural modeling based on AlphaFold2, complemented by molecular dynamics simulations, revealed possible differential interactions between CDKN1A and cyclins D1 and D3, predicting that CCND3-Thr283 becomes structurally buried upon CDKN1A binding, limiting its phosphorylation. Our findings provide novel mechanistic insights into how CDKN1A might regulate CCND3 stability, highlighting previously unexplored roles of cyclin D3-containing complexes in cell cycle arrest induced by butyrate.

cell biology↗

bioRxiv2025

Citrullination of TDP-43 is a key post-translation modification associated with structural and functional changes and progressive pathology in TDP-43 mouse models and human proteinopathies

TAR DNA-binding protein 43 (TDP-43) pathology is associated with a spectrum of clinical dementias including limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC). Post-translational modifications (PTM) are linked to TDP-43 toxic gain-of-function and cytoplasmic aggregation1-3. Phosphorylation remains the most investigated PTM and a standard criterion for determining pathology progression and clinical subclassification in TDP-43 proteinopathies4-7. However, full spectrum of PTMs on TDP-43 structure and biology remain unknown. Utilizing mass-spectrometry analysis we identified citrullination as a novel and irreversible "bona-fide" PTM of TDP-43 protein. We recognized peptidyl arginine deiminase 2 and 4 (PAD2 and PAD4) to mediate the conversion of arginine (R) to citrulline (citR) in vitro and demonstrated increased PAD2 and PAD4 expression and TDP-43 citrullination in a human wildtype TDP-43 mouse model (Tg (Thy1-TARDBP4). Transmission electron microscopy imaging analysis revealed citrullination induced vast structural changes while ThT analysis demonstrated altered aggregation kinetics of citrullinated (citR) TDP-43 protein. We further provided mechanistic evidence on reduced electrostatic and pi-pi interactions of citR TDP-43 Low Complexity Domain (LCD) with RNA, favoring liquid-solid phase separation and condensate formation. Generation and validation of several citR TDP-43 specific antibodies against several TDP-43 epitopes revealed epitope and domain-specific effects of citrullination on TDP-43 solubility in vivo. Importantly, we found distinct reactivities of citR TDP-43 antibodies shedding light into the contribution of epitope-specific properties of human citR TDP-43 to novel pathological citR TDP-43 assemblies in human brain tissue from LATE-NC, with or without comorbid Alzheimers disease neuropathologic changes (ADNC). These findings provided a unique look into the temporal citR TDP-43 signatures, and the potential clinical relevance associated with progression of pure LATE-NC and comorbid ADNC + LATE-NC. Collectively, these data reveal the existence of irreversible TDP-43 citrullination at targeted sites via induced PAD2/PAD4 activities, presenting a critical step in TDP-43 proteinopathy.

neuroscience↗

bioRxiv2025

Proximal relationships of moonlighting Proteins in Escherichia coli: a mathematical genomic perspective

Moonlighting proteins in Escherichia coli (E.coli) perform multiple independent functions without altering their primary amino acid sequence, challenging the "one gene-one enzyme" hypothesis. Bacterial proteins serve various functions, including host cell adhesion, extracellular matrix interaction, and immune modulation, while also supporting essential physiological processes within the bacteria. Identifying these proteins in pathogens and tracking their genetic changes is crucial for understanding bacterial survival and virulence. A quantitative understanding of these proteins is pivotal as it enables the identification of specific patterns and relationships between amino acid composition, protein stability, and functional versatility. This study quantitatively analyzes fifty E. coli moonlighting proteins, focusing on their structural and functional features. Key findings include variability in amino acid composition, with alanine predominating, and a preference for non-polar residues, which may enhance protein stability. Quantitative features analyses identified seven distinct proximal sets, reflecting the proteins spatial arrangements of amino acids, structural diversity, and functional roles in processes such as metabolism, stress response, and gene regulation. These results deepen our understanding of the multifunctionality of E. coli moonlighting proteins, indicating their adaptability and implications for bacterial survival and pathogenicity.

genomics↗

bioRxiv2024

Methuselah Proteins in Longevity: Unraveling Their Impact Through Mathematical Genomics

This study provides a quantitative and comprehensive analysis of 18 Methuselah (mth) protein variants from fruit flies, focusing on their evolutionary relationships, structural features, and functional roles in aging and longevity. Phylogenetic analysis identified two major clades of mth proteins, with the first clade indicating conserved functions across Drosophila species and the second clade reflecting gene duplication and diversification. The study found five distinct functional subclasses of mth proteins through amino acid frequency and poly-string analyses, linked to their structural diversity and role in longevity. Structural topology and post-translational modifications reveal similarities with G-protein-coupled receptors (GPCRs), suggesting that mth proteins are crucial for signal transduction and cellular health. Variability in propeptide cleavage sites and intrinsic protein disorder further highlight adaptive roles in signaling. The findings underscore the importance of a quantitative and comprehensive approach to studying Methuselah genes, offering insights into their functional versatility and evolutionary dynamics. This enhanced quantitative understanding contributes to advancing research on aging and longevity.

genomics↗

bioRxiv2024

Navigating the Fitness Landscapes of Plasmodium falciparum Dihydrofolate Reductase: Evolutionary Insights into Antifolate Resistance

The rapid emergence of drug resistance in malaria parasites poses a significant challenge to the efficacy of antifolate treatments. Traditional drug development approaches, which often rely on empirical screening with limited mechanistic insights, tend to overlook the complex evolutionary mechanisms that enable Plasmodium falciparum to evade drug inhibition while preserving enzyme functionality. In this study, we employed computational techniques to investigate the mutational landscape of dihydrofolate reductase (DHFR), focusing on regions essential for enzyme stability and resistance. Our analysis uncovered conserved residues essential for stability, mutation hotspots that enhance adaptability under drug pressure and co-evolving clusters revealing critical functional interdependencies. Through integrated approaches including mutational scanning, epistatic interaction modeling, and fitness trajectory mapping, we elucidated distinct evolutionary pathways that drive resistance. We were able to track the adaptive paths taken by wild-type residues upon mutation, revealing the steps required to reach high-fitness peaks within the rugged fitness landscape. These findings provide valuable insights into the molecular mechanisms of antifolate resistance. We suggest that future drug design should target co-evolving networks and conserved regions to support the development of next-generation therapies to overcome resistance.

biophysics↗

bioRxiv2024

Mapping DHPS Evolvability: Identification of Novel Evolutionarily Critical Sub-Structure through Evolutionary and Structural Analyses of DHPS

Protein evolution shapes pathogen adaptation-landscape, particularly in developing drug resistance. The rapid evolution of target proteins under antibiotic pressure leads to escape mutations leading to the problem of antibiotic resistance. A deep understanding of the evolutionary dynamics of antibiotic target proteins presents a plausible intervention strategy for disrupting the evolutionary trajectory of resistance. Mutations in Dihydropteroate synthase (DHPS), an essential folate pathway protein and a key target for sulfonamide antibiotics, result in reduced antibiotic binding, leading to resistance. Deploying an array of statistical analyses on the DHPS sequence-space and integrating those with deep mutational analysis and structure-based network-topology models we identified critical DHPS-subsequences. Our analysis of the frustration landscape of DHPS predicts how conformational and mutational changes shift the energy distributions within the DHPS substructures. Combining dimensionality reduction and optimality analysis we identified a substructure critical to DHPS evolvability, and computed its druggablity. Our integrated evolution and structure-informed framework identified a DHPS-substructure with significant evolutionary and structural impact. Targeting this region could constrain DHPS evolvability and disrupt the resistome, presenting a new avenue for antibiotic development and contributing to the broader effort to address the problem of antibiotic resistance.

biophysics↗

bioRxiv2024

Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy

Tauopathies, which include Alzheimers disease (AD) share a common defining factor, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequalae. We uncovered a novel PTM of tau, named citrullination, caused by peptidyl arginine deiminase (PAD) enzymes. PAD induced citrullination irreversibly converts arginine residues to citrulline, producing net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimers disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule binding repeat domain (MBR), and C-terminal domain (C-term) on full length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimers disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher phospho-tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.

neuroscience↗

bioRxiv2024

Molecular Genomic Insights into Melanoma Associated Proteins PRAME and BAP1

BackgroundMelanoma, a worldwide widespread skin cancer with over 325,000 yearly incidences, demands a thorough understanding of its molecular components to create effective therapeutics. This study looks at the PRAME (cutaneous melanoma-associated antigen) and BAP1 (gene controlling gene-environment interactions) proteins, which are important in melanoma development and are important for understanding the molecular landscape of melanoma. IntroductionWhile playing a crucial role in melanoma, the structural and functional characteristics of PRAME and BAP1 remain unidentified. This work tries to unravel their complexities by investigating conserved residues, sequence invariance, and other molecular characteristics that contribute to their importance in melanoma. Promising therapeutic targets for melanoma therapy are identified by analyzing these proteins at the molecular level. MethodsThe study makes extensive use of bioinformatics methods to analyze PRAME and BAP1, including sequence conservation, inherent disorder, polyglutamic acid presence, and polarity alterations. Established approaches are used to investigate residue changes and their effects on protein folding, aggregation, and interactions. ResultsPRAME and BAP1 conserved residues highlight their critical roles in protein function and interaction. Sequence invariance indicates the possibility of functional relevance and evolutionary conservation. In intrinsically disordered proteins (IDPRs), PRAME has enhanced intrinsic disorder and flexibility, whereas BAP1 has changed disorder-promoting residue sequences. Polyglutamic acid strings are found in both proteins, emphasizing their modulatory involvement in protein interactions. Protein folding and aggregation are influenced by polarity shifts, with a balanced distribution of acidic and basic residues preserving native structures. The ratios and distributions of amino acids, particularly neutral residues, have a profound influence on interactions and gene dysregulation. ConclusionPRAME and BAP1 structural and functional understanding pave the way for diagnostic and tailored treatment options in melanoma. Differences in residue alterations, polarity distributions, and amino acid ratios provide intriguing drug design options. This research contributes to a better knowledge of melanoma-associated two proteins, opening the path for novel diagnostic and therapy techniques in skin cancer and beyond.

bioinformatics↗

bioRxiv2023

The Distal-Proximal Relationships Among the Human Moonlighting Proteins: Evolutionary hotspots and Darwinian checkpoints

Moonlighting proteins, known for their ability to perform multiple, often unrelated functions within a single polypeptide chain, challenge the traditional "one gene, one protein, one function" paradigm. As organisms evolved, their genomes remained relatively stable in size, but the introduction of post-translational modifications and sub-strategies like protein promiscuity and intrinsic disorder enabled multifunctionality. Enzymes, in particular, exemplify this phenomenon, engaging in unrelated processes alongside their primary catalytic roles. This study employs a systematic, quantitative informatics approach to shed light on human moonlighting protein sequences. Phylogenetic analyses of human moonlighting proteins are presented, elucidating the distal-proximal relationships among these proteins based on sequence-derived quantitative features. The findings unveil the captivating world of human moonlighting proteins, urging further investigations in the emerging field of moonlighting proteomics, with the potential for significant contributions to our understanding of multifunctional proteins and their roles in diverse cellular processes and diseases.

genomics↗