Biology subjects

Yadav, A.

Publications and source records attributed to Yadav, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

A Vulnerable Subtype of Dopaminergic Neurons Drives Early Motor Deficits in Parkinson's Disease

In Parkinsons disease (PD), dopaminergic neurons (DANs) in the midbrain gradually degenerate, with ventral substantia nigra pars compacta (SNc) DANs exhibiting greater vulnerability. However, it remains unclear whether specific molecular subtypes of ventral SNc DANs are more susceptible to degeneration in PD, and if they contribute to the early motor symptoms associated with the disease. We identified a subtype of Sox6+ DANs, Anxa1+, which are selectively lost earlier than other DANs, and with a time course that aligns with the development of motor symptoms in MitoPark mice. We generated a knock-in Cre mouse line for Anxa1+ DANs and showed differential anatomical inputs and outputs of this population. Further, we found that the inhibition of transmitter release in Anxa1+ neurons led to bradykinesia and tremor. Therefore, Anxa1+ is not only a biomarker of a selectively vulnerable subtype of DANs, but is also sufficient to drive early motor symptoms in Parkinsons disease.

neuroscience↗

bioRxiv2024

ecPath detects ecDNA in tumors from histopathology images

Circular extrachromosomal DNA (ecDNA) can drive tumor initiation, progression and resistance in some of the most aggressive cancers and is emerging as a promising anti-cancer target. However, detection currently requires costly whole-genome sequencing (WGS) or labor-intensive cytogenetic or FISH imaging, limiting its application in routine clinical diagnosis. To overcome this, we developed ecPath (ecDNA from histopathology), a computational method for predicting ecDNA status from routinely available hematoxylin and eosin (H&E) images. ecPath implements a deep-learning method we call transcriptomics-guided learning, which utilizes both transcriptomics and H&E images during the training phase to enable successful ecDNA prediction from H&E images alone, a task not achievable with models trained on H&E images only. It is trained on more than 6,000 tumor whole-slide images from the TCGA cohort with the best performance in predicting ecDNA status in brain and stomach tumors (average AUC=0.78). ecPath revealed that ecDNA-positive tumors are enriched with pleomorphic, larger and high-density nuclei. Testing in an independent cohort, ecPath predicted ecDNA status of 985 pediatric brain tumor patients with an AUC of 0.72. Finally, we applied ecPath to identify ecDNA-positive tumors in the TCGA cohort for which no WGS data were available. Like WGS-based ecDNA-positive labels, the predicted ecDNA-positive status also identify poor prognoses for low grade glioma patients. These results demonstrate that ecPath enables the detection of ecDNA from routinely available H&E imaging alone and help nominate aggressive tumors with ecDNA to study and target it.

pathology↗

bioRxiv2024

Multi-laboratory Study Establishes Reproducible Methods for Plant-Microbiome Research in Fabricated Ecosystems

Inter-laboratory replicability is crucial yet challenging in microbiome research. Leveraging microbiomes to promote soil health and plant growth requires understanding underlying molecular mechanisms using reproducible experimental systems. In a global collaborative effort involving five laboratories, we aimed to help advance reproducibility in microbiome studies by testing our ability to replicate synthetic community assembly experiments. Our study compared fabricated ecosystems constructed using two different synthetic bacterial communities, the model grass Brachypodium distachyon, and sterile EcoFAB 2.0 devices. All participating laboratories observed consistent inoculum-dependent changes in plant phenotype, root exudate composition, and final bacterial community structure where Paraburkholderia sp. OAS925 could dramatically shift microbiome composition. Comparative genomics and exudate utilization linked the pH-dependent colonization ability of Paraburkholderia, which was further confirmed with motility assays. The study provides detailed protocols, benchmarking datasets, and best practices to help advance replicable science and inform future multi-laboratory reproducibility studies.

microbiology↗

bioRxiv2024

Lipid Droplet Targeting of ABHD5 and PNPLA3 I148M is required to promote liver steatosis

The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. /{beta} hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD bound protein that functions as a co-activator of Patatin Like Phospholipase Domain Containing 2 (PNPLA2; also known as Adipose triglyceride lipase, ATGL) the rate-limiting enzyme for TAG hydrolysis. The dysregulation of TAG hydrolysis is involved in various metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). We previously demonstrated that ABHD5 interacted with PNPLA3, a closely related family member to PNPLA2. Importantly, a common missense variant in PNPLA3 (I148M) is the greatest genetic risk factor for MASLD. PNPLA3 148M functions to sequester ABHD5 and prevent co-activation of PNPLA2, which has implications for initiating MASLD; however, the exact mechanisms involved are not understood. Here we demonstrate that LD targeting of both ABHD5 and PNPLA3 I148M is required for the interaction. Molecular modeling demonstrates important resides in the C-terminus of PNPLA3 for LD binding and fluorescence cross-correlation spectroscopy demonstrates that PNPLA3 I148M greater associates with ABHD5 than WT PNPLA3. Moreover, the C-terminus of PNPLA3 is sufficient for functional targeting of PNPLAs to LD and the interaction with ABHD5. In addition, ABHD5 is a general binding partner of LD-bound PNPLAs. Finally, PNPLA3 I148M targeting to LD is required to promote steatosis in vitro and in the liver. Overall results suggest that PNPLA3 I148M is a gain of function mutation and that the interaction with ABHD5 on LD is required to promote liver steatosis.

cell biology↗

bioRxiv2024

A stable 15-member bacterial SynCom promotes Brachypodium growth under drought stress

Rhizosphere microbiomes are known to drive soil nutrient cycling and influence plant fitness during adverse environmental conditions. Field-derived robust Synthetic Communities (SynComs) of microbes that mimic the diversity of rhizosphere microbiomes can greatly advance a deeper understanding of such processes. However, assembling stable, genetically tractable, reproducible, and scalable SynComs remains challenging. Here, we present a systematic approach using a combination of network analysis and cultivation-guided methods to construct a 15-member SynCom from the rhizobiome of Brachypodium distachyon. This SynCom incorporates diverse strains from five bacterial phyla and demonstrates strong stability both in vitro and in planta. Genomic analysis of the individual strains revealed that they encode multiple plant growth-promoting traits, some of which were validated by laboratory phenotypic assays. Additionally, most strains encoded genes both for the synthesis of osmoprotectants (trehalose and betaine) and Na+/K+ transporters. These traits likely enabled the resilience of Brachypodium to drought stress where plants amended with SynCom recovered better than without. We further observed preferential colonization of SynCom strains around root tips under stress, likely due to active interactions between plant root metabolites and bacteria. Our results represent significant progress towards building and testing stable model SynComs for a better understanding of plant-microbe interactions.

microbiology↗

bioRxiv2024

Self-organized coexistence of phage and a population of host colonies

Phages and bacteria coexist under widely different conditions, ranging from liquid cultures to oceans, soil, and the human gut. However, our models are typically limited to well-mixed liquid cultures governed by mass-action kinetics. Here, we suggest a modification to the Lotka-Volterra dynamics by including the formation of microcolonies. By analyzing the model in an open system with a steady influx of bacteria, we predict that the colony size distribution is power-low distributed with steeper exponents for the stronger external influx. In the realistic case where the phage attack rate to individual colonies is proportional to their radius, we obtain self-organization to a steady state where the maximal colony size is smaller for stronger external driving.

ecology↗

bioRxiv2024

Insertion and Anchoring of HIV-1 Fusion Peptide into Complex Membrane Mimicking Human T-cell

A fundamental understanding of how HIV-1 envelope (Env) protein facilitates fusion is still lacking. The HIV-1 fusion peptide, consisting of 15 to 22 residues, is the N-terminus of the gp41 subunit of the Env protein. Further, this peptide, a promising vaccine candidate, initiates viral entry into target cells by inserting and anchoring into human immune cells. The influence of membrane lipid reorganization and the conformational changes of the fusion peptide during the membrane insertion and anchoring processes, which can significantly affect HIV-1 cell entry, remains largely unexplored due to the limitations of experimental measurements. In this work, we investigate the insertion of the fusion peptide into an immune cell membrane mimic through multiscale molecular dynamics simulations. We mimic the native T-cell by constructing a 9-lipid asymmetric membrane, along with geometrical restraints accounting for insertion in the context of gp41. To account for the slow timescale of lipid mixing while enabling conformational changes, we implement a protocol to go back and forth between atomistic and coarse-grained simulations. Our study provides a molecular understanding of the interactions between the HIV-1 fusion peptide and the T-cell membrane, highlighting the importance of conformational flexibility of fusion peptides and local lipid reorganization in stabilizing the anchoring of gp41 into the targeted host membrane during the early events of HIV-1 cell entry. Importantly, we identify a motif within the fusion peptide critical for fusion that can be further manipulated in future immunological studies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/606381v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@d80eedorg.highwire.dtl.DTLVardef@bc2482org.highwire.dtl.DTLVardef@f715org.highwire.dtl.DTLVardef@15dba11_HPS_FORMAT_FIGEXP M_FIG Table of Content. C_FIG

biophysics↗

bioRxiv2024

A novel repressor-activator-competitor module comprising C2H2 zinc finger and NAC transcription factors regulates rice grain development

Grain size and quality are crucial agronomic traits. We have characterized a seed-preferential C2H2 zinc finger transcriptional repressor, ZOS1-15. Its overexpression, knock-down and knock-out plants indicated a negative control over grain size due to altered cell expansion. ZOS1-15 homodimerized and directly interacted with co-repressor TOPLESS and histone deacetylases to form a repression complex. ZOS1-15 also interacted with Mediator subunit MED14_1 and a seed-preferential transcriptional activator, ONAC024, with three alternatively spliced isoforms. The ectopic expression of ONAC024 negatively affected plant growth and development. Seed-preferential overexpression and knock-down plants showed ONAC024 as a positive regulator of grain length due to increased cell proliferation and expansion. CRES-T generated transgenic rice plants indicated a functional divergence amongst ONAC024 isoforms. Tandem interactions were observed between ONAC024-ONAC023-ONAC026-ONAC020. ZOS1-15 and ONAC024 functioned antagonistically to regulate grain amylose and SSP accumulation while ONAC023 affected only amylose. ZOS1-15 and ONAC024 directly regulated the expression of two SSP encoding genes. Binding of ONAC024 was competed by ONAC025-MADS29 complex. The seed-preferential overexpression of SS1/ ONAC025 resulted in decreased grain size and amylose content, but higher yield. This study proposes a repressor-activator-competitor module, wherein ZOS1-15, ONAC024, ONAC023, ONAC025 along with their interactors synergistically and antagonistically regulate multiple aspects of rice grain development.

plant biology↗

bioRxiv2024

Trace DNA from kill sites identifies predating tigers

Predation ecology and evidence-based conflict management strategies require reliable and accurate identification of individual predators. Identifying predators is, however, complex, as they are secretive and individual identification is difficult. Trace DNA that predators leave behind at kill sites might provide an effective strategy to identify them but remains poorly evaluated at scale. We use non-invasive genetic samples from kill sites to assess their utility for predator identification. We systematically investigated 198 livestock kills in two critical source tiger populations in central India: Kanha and Bandhavgarh Tiger Reserves. We collected 342 salivary swabs from carcasses, 33 scat and 395 shed hair samples as potential sources of predator DNA, and individual tigers were identified using up to 123 SNP markers. All three sample sources identified predator species with high success (>95%). We identified individuals (with at least one sample per kill site, based on >40 SNPs) at 86% of all kill sites where tigers were detected. Shed hair samples were most effective for individual identification, followed by saliva and scat. Sample source and sampling season were the primary determinants of the number of SNPs typed per sample and the success of individual identification. Based on the site and type of sample collection, we classify species and individuals into three categories: true predator (high confidence as predator), circumstantial predator (medium confidence) and predator uncertain (low confidence). Individuals were classified as a true predator at 72 sites, circumstantial predator at 34 sites and predator uncertain at 49 sites. Our protocol allowed us to differentiate between predators and scavengers, even when multiple tigers were detected at the same kill site. Surprisingly, [~]40% of Bandhavgarhs tigers were identified at at least one kill site. We suggest that when paired with systematic kill site investigation and sample collection, these methods can be effectively used to understand predation ecology better and facilitate evidence-based conflict management.

genetics↗

bioRxiv2024

Time course metabolomics and 13CO2 mapping establish BBX31/miP1b mediated metabolic readjustments conferring UV-B tolerance in Arabidopsis

B-box proteins (BBXs) are transcription factors that act as signal transducers in light signaling pathways. The microprotein BBX31/miP1b is known to play a positive role in promoting photomorphogenesis and stress tolerance under UV-B. However, the BBX31-mediated metabolic reprogramming to confer UV-B tolerance in plants is not well characterised. Here, we integrate metabolomics with kinetic 13CO2 tracer-based metabolic mapping, morpho-physiological and biochemical analysis to determine the metabolic rewiring in the UV tolerant genotypes. Our results suggest that BBX31 modulates the levels of photosynthetic compounds, reduces TCA cycle intermediates and enhances GS/GOGAT metabolic intermediates and secondary metabolic pathways. 13CO2 tracing studies established BBX31 modulates phenylpropanoid and GS/GOGAT pathways to divert flux towards the accumulation of UV-B protective metabolites phenylalanine, oxoproline, glutamine, and others. Although metabolomics indicated a higher accumulation of branch chain amino acids (BCAAs) under UV-B, they had negligible 13C incorporation, indicating their biosynthesis from pre-existing intermediates or via protein degradation. Further, we demonstrate that the exogenous application of phenylalanine, identified as one of the marker metabolites, confers tolerance to plants under UV-B. This study sheds light on BBX31-mediated metabolic rewiring under UV-B, which can assist targeted enrichment of metabolites and metabolic engineering to promote UV-B tolerance in plants. HighlightBBX31/miP1b modulates the levels of photosynthetic compounds, reduces TCA cycle intermediates and enhances GS/GOGAT metabolic intermediates to confer UV-B tolerance.

plant biology↗

bioRxiv2024

Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)

The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders. This discovery has resulted in a quest to identify high-affinity selective inhibitors of B0AT1 for the treatment of disorders of amino acid metabolism. Here we employed a medicinal chemistry approach to improve lead compounds that were identified in a previous high-throughput screen. This effort yielded a group of compounds that inhibited B0AT1 with IC50-values of 31-90 nM. High-resolution cryo-EM structures of B0AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a substantial movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.

biochemistry↗

bioRxiv2023

Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway.

In the developing vertebrate central nervous system, neurons and glia typically arise sequentially from common progenitors. Here, we report that the transcription factor Forkhead Box G1 (Foxg1) regulates gliogenesis in the mouse neocortex via distinct cell-autonomous roles in progenitors and in postmitotic neurons that regulate different aspects of the gliogenic FGF signalling pathway. We demonstrate that loss of Foxg1 in cortical progenitors at neurogenic stages causes premature astrogliogenesis. We identify a novel FOXG1 target, the pro-gliogenic FGF pathway component Fgfr3, that is suppressed by FOXG1 cell-autonomously to maintain neurogenesis. Furthermore, FOXG1 can also suppress premature astrogliogenesis triggered by the augmentation of FGF signalling. We identify a second novel function of FOXG1 in regulating the expression of gliogenic cues in newborn neocortical upper-layer neurons. Loss of FOXG1 in postmitotic neurons non-autonomously enhances gliogenesis in the progenitors via FGF signalling. These results fit well with the model that newborn neurons secrete cues that trigger progenitors to produce the next wave of cell types, astrocytes. If FGF signalling is attenuated in Foxg1 null progenitors, they progress to oligodendrocyte production. Therefore, loss of FOXG1 transitions the progenitor to a gliogenic state, producing either astrocytes or oligodendrocytes depending on FGF signalling levels. Our results uncover how FOXG1 integrates extrinsic signalling via the FGF pathway to regulate the sequential generation of neurons, astrocytes, and oligodendrocytes in the cerebral cortex.

neuroscience↗

bioRxiv2023

Identifying Selectivity Filters in Protein Biosensor for Ligand Screening

Specialized sensing mechanisms in bacteria enable the identification of cognate ligands with remarkable selectivity in highly xenobiotic-polluted environments, where these ligands are utilized as energy sources. Here, via an integrated all-atom computer simulation, biochemical assay and isothermal titration calorimetry approaches we determine the molecular basis of MopR, a phenol biosensors complex selection process of ligand entry. Our results reveal a set of strategically placed selectivity filters along the ligand entry pathway of MopR. These filters act as checkpoints, screening diverse aromatic ligands at the protein surface based on their chemical features and sizes. Ligands meeting specific criteria are allowed to enter the sensing site in an orientation-dependent manner. Sequence and structural analyses demonstrate the conservation of this ligand entry mechanism across the sensor class, with individual amino acids along the selectivity filter path playing a critical role in ligand selection. Together, this investigation highlights the importance of interactions with the ligand entry pathway, in addition to interactions within the binding pocket, for achieving ligand selectivity in biological sensing. The findings enhance our understanding of ligand selectivity in bacterial phenol biosensors and provide insights for the rational expansion of the biosensor repertoire, particularly for the biotechnologically relevant class of aromatic pollutants.

biochemistry↗

bioRxiv2023

RNA- and ATAC-sequencing Reveals a Unique CD83+ Microglial Population Focally Depleted in Parkinson's Disease

All brain areas affected in Parkinsons disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A-expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

neuroscience↗

bioRxiv2023

Chimera alert! The threat of chimeric sequences causing inaccurate taxonomic classification of phytoplasma strains

The 16S rRNA gene is a primary marker used to study bacterial taxonomy, particularly for bacteria with Candidatus status, where it serves as a primary reference sequence for identification. Despite its usefulness, ensuring the authenticity of publicly available sequences has always posed a challenge. To address this issue, multiple tools and databases with curated collections of reference 16S rRNA gene sequences were established. However, even with these efforts, many sequence chimeras still exist. These chimeric gene sequences are formed by the fusion of sequence parts from multiple organisms and can arise from errors during PCR amplification or sequencing. The objective of this study was to identify chimeric sequences from a dataset of over 4500 phytoplasma 16S rRNA gene sequences using multiple tools. The tools ChimeraSlayer and UCHIME identified 12 and 11 chimeric sequences, respectively. Notably, these sequences included the reference 16S rRNA gene sequence of Ca. Phytoplasma wodyetiae strain Bangi-2 (KC844879) and Ca. Phytoplasma allocasuarinae (AY135523). The studys outcomes indicated the existence of chimeric 16S rRNA gene sequences, emphasizing the threat posed by such sequences in correctly assigning taxonomic status to phytoplasma strains. These findings underscore the importance of rigorously verifying the authenticity of 16S rRNA gene sequences to ensure their accuracy in identifying and classifying bacterial species.

microbiology↗

bioRxiv2023

At least 10 genes on chromosome 5 of Candida albicans are downregulated in concert to control cell wall and to confer adaptation to caspofungin

Candida albicans is part of normal microbiota, however, can cause superficial and life threatening infection in immune-compromised individuals. Drugs from echinocandin (ECN) class that disrupt cell wall synthesis, are being used as a major treatment strategy against candidiasis. As the use of ECNs for the treatment of candidiasis is increasing, resistance against ECNs is also emerging. Previously, we reported involvement of 5 chromosome 2 (Ch2) genes in adaptation to ECN drugs. Here, we explored 22 candidate-genes on Ch5 that are consistently downregulated in independent mutants adapted to caspofungin (CAS), for their role in ECN adaptation. We also compared cell wall remodelling in CAS-adapted mutants and in 10 knockouts (KOs) from Ch5. Independent KO experiments as combined with broth microdilution assay, demonstrated that, as expected, 10 out of 22 Ch5 genes decrease ECN susceptibility by controlling the levels of three major components of the cell wall, glucan, mannan, and chitin. Some KOs decreased glucan or increased chitin or both. Similar cell wall remodelling, decreased glucan and increased chitin, was found in CAS-adapted mutants with no ploidy change. Some other KOs had no glucan change, but increased the level of either mannan or chitin. Our results identify the function of two uncharacterized genes, orf19.970 and orf19.4149.1, and expand the functions of DUS4, RPS25B, UAP1, URA7, RPO26, HAS1, and CKS1. The function of CHT2, as negative regulator of ECN susceptibility, has been previously established. Importantly, half of the above genes are essential indicating that essential processes are involved in cell wall remodelling for adaptation to ECNs. Also important, orf19.970 and orf19.4149.1 have no human orthologues. Finally, our work shows that multiple mechanisms are used by C. albicans cells to remodel cell wall in order to adapt to CAS. This work continues to identify common pathways that are involved in drug adaptation, as well as new genes controlling ECN susceptibility and reveals new targets for development of novel antifungal drugs.

genetics↗

bioRxiv2023

Comparative Transcriptomics and Genomics from Continuous Axenic Media Growth Identifies Coxiella burnetii Intracellular Survival Strategies

Coxiella burnetii (Cb) is an obligate intracellular pathogen in nature and the causative agent of acute Q fever as well as chronic diseases. In an effort to identify genes and proteins crucial to their normal intracellular growth lifestyle, we applied a "Reverse evolution" approach where the avirulent Nine Mile Phase II strain of Cb was grown for 67 passages in chemically defined ACCM-D media and gene expression patterns and genome integrity from various passages was compared to passage number one following intracellular growth. Transcriptomic analysis identified a marked downregulation of the structural components of the type 4B secretion system (T4BSS), the general secretory (sec) pathway, as well as 14 out of 118 previously identified genes encoding effector proteins. Additional downregulated pathogenicity determinants genes included several chaperones, LPS, and peptidoglycan biosynthesis. A general marked downregulation of central metabolic pathways was also observed, which was balanced by a marked upregulation of genes encoding transporters. This pattern reflected the richness of the media and diminishing anabolic and ATP-generation needs. Finally, genomic sequencing and comparative genomic analysis demonstrated an extremely low level of mutation across passages, despite the observed Cb gene expression changes following acclimation to axenic media.

microbiology↗

bioRxiv2023

Characterizing the Interactions of Cell Membrane-Disrupting Peptides with Lipid-Functionalized Single-Walled Carbon Nanotube Systems for Antimicrobial Screening

Lipid-functionalized single-walled carbon nanotubes (SWNTs) have garnered significant interest for their potential use in a wide range of biomedical applications. In this work, we used molecular dynamics simulations to study the equilibrium properties of SWNTs surrounded by the phosphatidylcholine (POPC) corona phase, and their interactions with three cell membrane disruptor peptides: colistin, TAT peptide, and crotamine-derived peptide. Our results show that SWNTs favor asymmetrical positioning within the POPC corona, so that one side of the SWNT, covered by the thinnest part of the corona, comes in contact with charged and polar functional groups of POPC and water. We also observed that colistin and TAT insert deeply into POPC corona, while crotamine-derived peptide only adsorbs to the corona surface. Compared to crotamine-derived peptide, colistin and TAT also induce larger perturbations in the thinnest region of the corona, by allowing more water molecules to directly contact the SWNT surface. In separate simulations, we show that three examined peptides exhibit similar insertion and adsorption behaviors when interacting with POPC bilayers, confirming that peptide-induced perturbations to POPC in conjugates and bilayers are similar in nature and magnitude. Furthermore, we observed correlations between the peptide-induced structural perturbations and the near-infrared emission of the lipid-functionalized SWNTs, which suggest that the optical signal of the conjugates transduces the morphological changes in the lipid corona. Overall, our findings indicate that lipid-functionalized SWNTs could serve as simplified cell membrane model systems for pre-screening of new antimicrobial compounds that disrupt cell membranes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/525557v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@4c5645org.highwire.dtl.DTLVardef@1b3cd30org.highwire.dtl.DTLVardef@1643c6corg.highwire.dtl.DTLVardef@1bb096e_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗