Biology subjects

Rath, S. L.

Publications and source records attributed to Rath, S. L..

6 recordsLinked to original sources

bioRxiv2026

Chain-Length-Dependent Interactions of Polyethylene Nanoplastics with Human Catalase reveals Size based Nanoplastic Toxicity

Nanoplastic contamination is increasingly recognized as a biochemical stressor, yet the molecular determinants governing how polymer fragment size dictates protein-level interactions remain poorly understood. Here, we combine molecular docking and all-atom molecular dynamics simulations to characterize the interaction of polyethylene (PE) oligomers of increasing length (n = 3, 5, 7, and 14 repeat units) with human catalase, a tetrameric heme enzyme central to cellular antioxidant defense. Single-chain simulations reveal that short PE fragments (3-, 5-, and 7-mer) migrate from an initial domain-connector pose toward a heme-proximal, previously characterized inhibitor-binding site, whereas the 14-mer remains kinetically confined to a peripheral surface site, implicating short-chain PE as a potential catalase inhibitor. In multichain corona systems, backbone dynamics show a non-monotonic, chain-length-dependent destabilization, with the 3- and 5-mer inducing the greatest structural perturbation and the 14-mer best preserving native-like dynamics despite forming an extensive, percolating surface network across all four subunits. MM-PBSA free energy decomposition identifies van der Waals interactions as the dominant thermodynamic driver of binding, while electrostatic surface mapping indicates that cationic surface patches instead govern long-range spatial targeting of PE chains. These findings establish a framework linking nanoplastic fragment size to protein-level toxicity, with direct implications for assessing the biochemical risk of environmentally weathered polyethylene.

biophysics↗

bioRxiv2025

Neural Network-Enhanced Investigation of Ferroptosis and Druggability in Early-Onset Alzheimers Disease

BackgroundAlzheimers disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-{beta} protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. MethodsThis study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC-0.92) in the analysis. ResultsThe findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses were in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress, contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. ConclusionThis study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimers disease.

genomics↗

bioRxiv2021

Scanning the RBD-ACE2 molecular interactions in Omicron variant

The emergence of new SARS-CoV-2 variants poses a threat to the human population where it is difficult to assess the severity of a particular variant of the virus. Spike protein and specifically its receptor binding domain (RBD) which makes direct interaction with the ACE2 receptor of the human has shown prominent amino acid substitutions in most of the Variants of Concern. Here, by using all-atom molecular dynamics simulations we compare the interaction of Wild-type RBD/ACE2 receptor complex with that of the latest Omicron variant of the virus. We observed a very interesting diversification of the charge, dynamics and energetics of the protein complex formed upon mutations. These results would help us in understanding the molecular basis of binding of the Omicron variant with that of SARS-CoV-2 Wild-type. TOC Graphics O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/472253v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1e35dceorg.highwire.dtl.DTLVardef@23a441org.highwire.dtl.DTLVardef@1f4b7e3org.highwire.dtl.DTLVardef@1549a1c_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2021

Molecular Insights into the Differential Dynamics of SARS-CoV-2 Variants of Concern (VOCs)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected the lives and livelihood of millions of individuals around the world. It has mutated several times after its first inception, with an estimated two mutations occurring every month. Although we have been successful in developing vaccines against the virus, emergence of variants has enabled it to escape therapy. Few of the generated variants are also reported to be more infectious than the wild-type (WT). In this study, we analyze the attributes of all RBD/ACE2 complexes for the reported VOCs, namely, Alpha, Beta, Gamma, and Delta through computer simulations. Results indicate differences in orientation and binding energies of the VOCs from the WT. Overall, it was observed that electrostatic interactions play a major role in the binding of the complexes. Detailed residue level energetics revealed that the most prominent changes in interaction energies were seen particularly at the mutated residues which were present at RBD/ACE2 interface. We found that the Delta variant is one of the most tightly bound variants of SARS-CoV-2 with dynamics similar to WT. High binding affinity of RBD towards ACE2 is indicative of an increase in the viral transmission and infectivity. The details presented in our study would prove extremely useful for the design and development of effective therapeutic strategies for the emerging variants of the virus.

biophysics↗

bioRxiv2021

How does temperature affect the dynamics of SARS-CoV-2 M proteins? Insights from Molecular Dynamics Simulations

Enveloped viruses, in general, have several transmembrane proteins and glycoproteins, which assist the virus in entry and attachment onto the host cells. These proteins also play a significant role in determining the shape and size of the newly formed virus particles. The lipid membrane and the embedded proteins affect each other in non-trivial ways during the course of the viral life cycle. Unravelling the nature of the protein-protein and protein-lipid interactions, under various environmental and physiological conditions, could therefore prove to be crucial in development of therapeutics. Here, we study the M protein of SARS-CoV-2 to understand the effect of temperature on the properties of the protein-membrane system. The membrane embedded dimeric M proteins were studied using atomistic and coarse-grained molecular dynamics simulations at temperatures ranging between 10 and 50 {degrees}C. While temperature induced fluctuations should be monotonic, we observe a steady rise in the protein dynamics up to 40 {degrees}C, beyond which it surprisingly reverts back to the low temperature behaviour. Detailed investigation reveals disordering of the membrane lipids in the presence of the protein, which induces additional curvature around the transmembrane region. Coarse-grained simulations indicate temperature dependent aggregation of M protein dimers. Our study clearly indicates that the dynamics of membrane lipids and integral M protein of SARS-CoV-2 enables it to better associate and aggregate only at a certain temperature range (i.e., ~30 to 40 {degrees}C). This can have important implications in the protein aggregation and subsequent viral budding/fission processes.

biophysics↗

bioRxiv2020

Investigation of the effect of temperature on the structure of SARS-Cov-2 Spike Protein by Molecular Dynamics Simulations

Statistical and epidemiological data imply temperature sensitivity of the SARS-CoV-2 coronavirus. However, the molecular level understanding of the virus structure at different temperature is still not clear. Spike protein is the outermost structural protein of the SARS-CoV-2 virus which interacts with the Angiotensin Converting Enzyme 2 (ACE2), a human receptor, and enters the respiratory system. In this study, we performed an all atom molecular dynamics simulation to study the effect of temperature on the structure of the Spike protein. After 200ns of simulation at different temperatures, we came across some interesting phenomena exhibited by the protein. We found that the solvent exposed domain of Spike protein, namely S1, is more mobile than the transmembrane domain, S2. Structural studies implied the presence of several charged residues on the surface of N-terminal Domain of S1 which are optimally oriented at 10-30 {degrees}C. Bioinformatics analyses indicated that it is capable of binding to other human receptors and should not be disregarded. Additionally, we found that receptor binding motif (RBM), present on the receptor binding domain (RBD) of S1, begins to close around temperature of 40 {degrees}C and attains a completely closed conformation at 50 {degrees}C. The closed conformation disables its ability to bind to ACE2, due to the burying of its receptor binding residues. Our results clearly show that there are active and inactive states of the protein at different temperatures. This would not only prove beneficial for understanding the fundamental nature of the virus, but would be also useful in the development of vaccines and therapeutics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/145086v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1e631eeorg.highwire.dtl.DTLVardef@1d83278org.highwire.dtl.DTLVardef@d98d3borg.highwire.dtl.DTLVardef@c75b7f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIStatistical and epidemiological evidence show that external climatic conditions influence the SARS-CoV infectivity, but we still lack a molecular level understanding of the same. C_LIO_LIHere, we study the influence of temperature on the structure of the Spike glycoprotein, the outermost structural protein, of the virus which binds to the human receptor ACE2. C_LIO_LIResults show that the Spikes S1 domain is very sensitive to external atmospheric conditions compared to the S2 transmembrane domain. C_LIO_LIThe N-terminal domain comprises of several solvent exposed charged residues that are capable of binding to human proteins. The region is specifically stable at temperatures ranging around 10-30{degrees} C. C_LIO_LIThe Receptor Binding Motif adopts a closed conformation at 40{degrees}C and completely closes at higher temperatures making it unsuitable of binding to human receptors C_LI

biophysics↗