Biology subjects

Zhu, Z.

Publications and source records attributed to Zhu, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Cytopenias and Functional Defects in a Novel Murine Model of VPS45 Severe Congenital Neutropenia

Mutations in the VPS45 gene are associated with a rare form of severe congenital neutropenia (SCN5), a life-threatening inherited error of immunity. We developed and characterized a novel mouse model of SCN5 by CRISPR/Cas9-mediated knock-in of pathogenic VPS45 E238K and T224N mutations. Both Vps45 mutations led to decreased protein expression in bone marrow cells. In vivo phenotyping demonstrated a non-Mendelian genetic distribution with reduced numbers of knock-in homozygotes Vps45E238K. Vps45E238K knock-in homozygous mice showed reduced body weight, reduced body condition with age, and increased mortality. As in human SCN5, Vps45E238K knock-in homozygotes demonstrated neutropenia and lymphopenia. Functionally, Vps45E238K knock-in homozygote neutrophils exhibited increased lipopolysaccharide-induced apoptosis and decreased peroxide production, phagocytic capacity and in vivo cell migration, phenocopying the functional defects reported in patients. Vps45T224N knock-in homozygous mice showed a milder phenotype or no abnormalities. In conclusion, this mouse model phenocopies, in part, human SCN5. It provides a novel platform for future studies of the pathophysiology of defects in neutrophil number and function in human SCN5, potential therapies for the disease, and the biochemistry and cell biology of VPS45. Summary statementWe report a mouse model of severe congenital neutropenia due to VPS45 missense mutations. It represents the first animal model of human neutropenia due to a defect in intracellular trafficking.

immunology↗

bioRxiv2026

SteerAF: Distogram-based Steering of AlphaFold2 toward Alternative Conformations

End-to-end structure predictors, such as AlphaFold2, typically output only the dominant conformational state of a given protein, which is biased by the training dataset. Existing strategies for recovering alternative conformations are often computationally expensive and offer limited biological interpretability. Here, we present SteerAF, an inference-time optimization framework based on AlphaFold2 that leverages information encoded in the distogram derived from deep multiple sequence alignments (MSAs) to predict alternative protein conformations. Across four benchmark datasets, SteerAF matches or surpasses existing methods in predicting alternative conformations for the majority of systems. Sparse MSA-feature modifications generated via block gradient ascent exhibit a strong correlation with experimentally characterized functional residues, recovering them with approximately 50% precision in the tested proteins. Furthermore, SteerAF enables effective decoy selection in the absence of experimental structures, and its predictions can serve as seed structures for molecular dynamics simulations to map conformational landscapes. Thus, SteerAF provides an efficient and interpretable approach for predicting alternative conformations, offering a framework that can be extended to other similar predictors and problems.

bioinformatics↗

bioRxiv2026

Hemoglobin C is prone to oxidative denaturation, resulting in red blood cell membrane damage in HbSC disease

Sickle-hemoglobin-C (HbSC) sickle cell disease is characterized by RBC dehydration (xerocytosis), which promotes polymerization of HbS. HbSC causes substantial morbidity despite lower sickling potential than HbSS, suggesting a critical detrimental role of HbC in the disease pathophysiology. We derived HbCC mice by interbreeding our HbSC mice, which demonstrated a similar RBC phenotype of xerocytosis as humans with HbCC. We compared RBCs from HbCC, HbSC, and HbSS mice. Oxidized ferryl (Fe4+)-Hb, and its oxidative-denaturation, which results in hemichrome formation (Heinz-bodies), was most pronounced in HbCC>HbSC>HbSS, despite significantly higher reactive oxygen species in HbSS, illustrating a higher propensity of HbC to denaturation than HbS. RBC deformability followed a similar pattern, with Elongation Index lowest in HbCC<HbSC<HbSS. Next, we determined if RBC from HbSC patients on hydroxyurea showed improved membrane damage. Hydroxyurea treatment reduced Heinz-body formation and improved RBC deformability, despite negligible/modest fetal hemoglobin (HbF) induction, compared to non-hydroxyurea HbSC controls. The antioxidant quercetin showed a similar reduction in Heinz-body burden and improvement in RBC deformability as hydroxyurea, without affecting Hb or HbF concentration, reticulocyte count, or RBC xerocytosis. HbC-driven oxidative denaturation and membrane damage represent important contributors of RBC dysfunction in HbSC disease; hence, oxidative membrane injury could be targeted besides antisickling approaches.

cell biology↗

bioRxiv2026

Architecture of a portal complex embedded in the poxvirus core

Gene transcription within the viral core is a unique feature of poxvirus replication. Following entry into the cytoplasm, the poxvirus core dissociates from the lateral bodies and undergoes expansion, functioning as a compartment for early transcription. However, the mechanisms governing molecular exchange between the viral core and the host cytoplasm remain poorly understood. Here, we determine the structures of the portal complex and its pore on the poxvirus core at 7.1 [A] and 4.9 [A] resolution, respectively, using cryo-electron tomography and sub-tomogram averaging. The pore is assembled from three viral proteins, E8, E6, and L3, for which we constructed an atomic model. Structural and channel analyses reveal that the pore satisfies the geometric and electrostatic requirements for the transport of RNA and smaller negatively charged molecules, while excluding double-stranded DNA and cytosolic DNA sensors. Together, our findings establish a structural framework for understanding the assembly and function of the poxvirus portal complex and identify potential targets for antiviral intervention.

biophysics↗

bioRxiv2026

S-nitrosylation of protein kinase A is required for its activation by GPCRs

Stimulation of many G protein-coupled receptors (GPCRs) increases cyclic adenosine monophosphate (cAMP) and nitric oxide (NO). While cAMP-dependent activation of protein kinase A (PKA) is a central regulatory mechanism, a parallel role for NO in GPCR transduction has not been established. Here we show that upon stimulation of multiple GPCRs in heart, brain, and fat, the regulatory subunits of PKA undergo enzymatic S-nitrosylation by SNO-CoA-assisted nitrosylase (SCAN). S-nitrosylation by SCAN is required for dissociation of PKA holoenzymes and activation of PKA. In transgenic and cardiovascular disease models, impaired adrenergic stimulation is identified with deficient S-nitrosylation of PKA, which can be rescued by the drug sodium nitroprusside. Our work suggests a new understanding of GPCR physiology with direct application to the clinical setting.

physiology↗

bioRxiv2026

Combinatorial screening of nanoparticles for nose-to-brain RNA delivery to modulate neuroinflammation after traumatic brain injury

Traumatic brain injury (TBI)-induced neuroinflammation can evolve over weeks or months, contributing to ongoing secondary damage and worsening neurological recovery. RNA-based therapeutics hold great potential to regulate inflammatory signaling, but delivery to the brain remains challenging because of the blood brain barrier. Intranasal administration offers a direct non-invasive route for brain access but is often limited by low delivery efficiency. Here we constructed a combinatorial library of DNA-barcoded 103 lipid nanoparticles by varying lipid components with diverse headgroup chemistries and bioreactive moieties. A high throughput screening of these nanoparticles in vivo following intranasal administration led to the identification of top candidates with highest brain accumulation. Intranasal delivery of an antagomir targeting microRNA-9-5p loaded nanoparticle effectively reduced cerebral microRNA-9-5p levels, suppressed inflammatory markers, and improved neurological outcomes in TBI. These results demonstrate a systematic approach for optimizing intranasal lipid nanoparticle design and support the feasibility of RNA delivery to modulate neuroinflammation after brain injury.

bioengineering↗

bioRxiv2026

simCRISPR: Modeling experimental complexity in pooled CRISPR screens

Pooled CRISPR screens are widely used to investigate gene function and uncover genetic interactions. However, benchmarking computational methods for detecting gene-by-environment (GxE) interactions remains difficult because ground truth is rarely available and existing simulation tools are not designed for GxE screening contexts. To address this, we developed simCRISPR, a flexible simulation framework for generating pooled CRISPR screen data under complex experimental designs. Using simulated datasets informed by empirical CRISPR screen designs, we evaluated commonly used analysis methods, comparing normalization strategies based on safe-harbor versus non-targeting sgRNAs and assessing empirical log2FC thresholds as an additional effect-size criterion. We found that safe-harbor-based normalization improved interaction detection when DNA damage-related effects were present, particularly when combined with empirical log2FC thresholding for DESeq2. Application of this workflow to a doxorubicin GxE screen further showed that safe-harbor-based normalization reduced bias in log2FC distributions and identified additional biologically relevant candidates. simCRISPR is available at https://github.com/bachergroup/simCRISPR.

bioinformatics↗

bioRxiv2026

Neuromodulation of Foxp2+ hypothalamic neurons induces therapeutic hypothermia

The inability to selectively trigger therapeutic hypothermia independent of environmental cooling has hindered causal analysis of its broader physiological benefits. Here, we employed P57, a natural product that pharmacologically induces therapeutic hypothermia circumventing external cold stress, to identify the neuronal substrates underlying hypothermia-induced antitumor effects. Integrating functional ultrasound imaging, activity-dependent neuronal labeling, and single-nucleus RNA sequencing, we identify a previously unrecognized population of Foxp2 neurons in the medial preoptic area (MPA) that are selectively activated by P57. Inhibition of MPA Foxp2+ neurons abolishes P57-induced hypothermia, whereas the paraventricular hypothalamus (PVH) serves as a critical downstream node. Importantly, targeted activation of MPA Foxp2 neurons is sufficient to induce sustained hypothermia, suppress systemic metabolism, and inhibit tumor growth, providing causal evidence that neuronally driven reductions in core body temperature can exert antitumor effects. Together, these findings establish MPA Foxp2 neurons as a controllable node for therapeutic hypothermia induction and demonstrate that neuromodulation of defined neuronal populations can achieve therapeutic benefit by directly controlling physiological states.

neuroscience↗

bioRxiv2026

A novel reporter mouse for astrocyte-derived extracellular vesicles reveals trafficking of cargo to neuronal mitochondria

Extracellular vesicles (EVs) mediate intercellular transfer of lipids, proteins, and nucleic acids between nearly all cell types. We previously showed that astrocyte-derived EVs modulate neuronal mitochondria in vitro, but whether endogenous astrocytic EVs are trafficked to neuronal mitochondria in vivo remained unknown. To address this, we generated an EV reporter mouse, Aldh1l1-Cre; CD9-tGFPfl/fl, in which astrocyte-secreted EVs are labeled with a CD9-turboGFP fusion protein (CD9-tGFP). Astrocyte-specific expression of CD9-tGFP was verified in brain tissue and isolated EVs, comprising 13.2 {+/-} 1.6% of total brain EVs. In primary glial cultures, CD9-tGFP was restricted to astrocytes, localizing to vesicular compartments and cell protrusions (filopodia and cilia), with 89.3 {+/-} 2.2% of astrocyte-derived EVs carrying the label. These EVs were enriched with the sphingolipid ceramide, consistent with its co-distribution with CD9-tGFP in astrocytic cell protrusions. In the cortex, hippocampus, and cerebellum, CD9-tGFP was predominantly detected in astrocytic processes co-labeled with GLAST1 and GFAP, forming contacts with laminin-positive capillaries and parvalbumin-positive neurons. CD9-tGFP-labeled EVs were detected inside capillaries and neurons, and super-resolution STED microscopy revealed partial overlap with neuronal mitochondria. Live-cell spinning disk confocal imaging and AI-assisted proximity analysis confirmed uptake of CD9-tGFP EVs by neuronal cells and trafficking of their cargo to mitochondria in vitro. Biochemical isolation of synaptic and non-synaptic mitochondria confirmed EV-derived cargo on mitochondria in vivo, with 3-fold higher association of CD9-tGFP with synaptic than non-synaptic mitochondria. Together, these findings validate the Aldh1l1-Cre; CD9-tGFPfl/fl reporter mouse as a powerful tool for tracking astrocyte-derived EVs in vivo and provide direct evidence that their cargo is preferentially trafficked to synaptic mitochondria. Graphical AbstractAstrocyte-derived extracellular vesicles target neuronal mitochondria in vivo O_FIG O_LINKSMALLFIG WIDTH=156 HEIGHT=200 SRC="FIGDIR/small/718987v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@174d92aorg.highwire.dtl.DTLVardef@5d8248org.highwire.dtl.DTLVardef@114483borg.highwire.dtl.DTLVardef@924d55_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

A genome-wide in vivo screen reveals fitness pathways required for streptococcal infective endocarditis

Infective endocarditis (IE) is a life-threatening disease most often caused by blood-borne bacteria that infect previously damaged cardiac tissue. Despite the importance of this disease, the genetic basis for IE virulence remains poorly defined. Here, we present the first genome-wide in vivo analysis of bacterial fitness in a vertebrate model of IE. We identified 146 genes in Streptococcus sanguinis required for IE fitness, the majority of which had not previously been linked to endocarditis. These determinants cluster into conserved metabolic, cell envelope, transport, and regulatory pathways, representing a vast reservoir of potential targets for novel antimicrobial intervention. A subset of these genes was examined in Streptococcus mutans; all were found to be essential for IE fitness in this distantly related oral species as well, suggesting broad conservation. Using experimental evolution, we further show that disruption of key fitness pathways triggers reproducible compensatory "bypass" mechanisms that reveal the inherent physiological constraints of the IE fitness landscape and identify vulnerable nodes for multi-target drug strategies. Together, these findings redefine streptococcal infective endocarditis as a disease shaped by conserved bacterial fitness networks that may be exploited for therapeutic development. HighlightsO_LIA genome-wide in vivo screen identified 146 Streptococcus sanguinis genes required for infective endocarditis fitness. C_LIO_LI94% of these genes represent previously unrecognized determinants of endocarditis. C_LIO_LIMultiple pathways--including CoA biosynthesis, the shikimate pathway, and rhamnan synthesis--are required for cardiac colonization. C_LIO_LIA subset of infective endocarditis fitness factors are conserved between S. sanguinis and S. mutans, with species-specific adaptations. C_LIO_LIExperimental evolution revealed compensatory metabolic networks that buffer IE fitness defects. C_LI

genetics↗

bioRxiv2026

Ceramide-rich extracellular vesicles as pathogenic biomarkers in traumatic brain injury

Extracellular vesicles (EVs) contribute to the damage caused by traumatic brain injury (TBI) and can cross the blood-brain barrier (BBB). We analyzed plasma-derived EVs from human TBI patients to identify factors potentially contributing to TBI pathology. EVs were isolated using membrane affinity (ExoEasy) and size exclusion chromatography (iZone), both yielding CD9(+) and CD63(+) EVs with minimal contamination by serum albumin and apolipoprotein. Immunoblotting detected GFAP in TBI but not control EVs, indicating astrocyte-derived EVs crossing the BBB. Proteomic analysis and immunoblotting of EVs from TBI samples identified C-reactive protein and 14-3-3 proteins, which were not detected in control EVs, indicating inflammation associated with TBI. Lipidomic analysis showed ceramide enrichment in TBI EVs, validated by anti-ceramide immunoprecipitation. In a mouse closed head-controlled cortical impact model, brain EVs similarly showed elevated ceramide, confirming ceramide-rich EV release after TBI. Immunocytochemistry localized acid sphingomyelinase (ASM), a ceramide-generating enzyme, to ependymal cilia, suggesting these sites as a potential source of EVs. This was further supported by the detection of ASM in both brain- and plasma-derived EVs, along with the ciliary marker Arl13b in the brain. To assess function, we treated murine neuronal (N2a) cells with TBI EVs. Transcriptomics and STRING analyses revealed enrichment of mitochondrial-associated transcripts. Immunoblotting showed increased p53 and voltage-dependent anion channel 1 (VDAC1), which mediate ceramide-induced apoptosis. Seahorse assays showed that TBI EVs suppressed glycolysis, as indicated by reduced ECAR, while mitochondrial respiration (OCR) remained unchanged. LDH assays further indicated that TBI EVs were more neurotoxic than control EVs. Together, these findings identify ceramide-rich EVs as plasma biomarkers of TBI-induced inflammation, potential mediators of neuronal mitochondrial dysfunction, and pharmacological targets to prevent TBI-induced damage.

neuroscience↗

bioRxiv2026

Versatility of Campylobacter jejuni Bf extracellular vesicles in regulating adaptation and virulence under combined thermal and oxidative stress

The high prevalence of aerotolerant human Campylobacter jejuni isolates suggests a correlation between the ability to survive in aerobic conditions, virulence and resistance to harsh stress conditions. However, the mechanisms are still unclear. Here, we investigated the role of bacterial extracellular vesicles (bEVs) in the adaptation of the clinical aerotolerant C. jejuni Bf strain to thermal and oxidative stress. We show that C. jejuni Bf survives and actively multiplies under this combined stress. Stress exposure induced cell rounding and loss of motility, remodeling of membrane composition, decreased membrane fluidity, and metabolic reprogramming with increased intracellular ATP levels. Lipidomic analyses further revealed that bEVs composition is markedly different from that of the parent membranes indicating that vesicle formation is selective and regulated. Although bEVs were produced in similar amounts under both microaerophilic and stress conditions, stress exposure generated significantly larger vesicles with greater diameter and dry mass, and altered their protein and lipid profiles. bEVs derived from stressed cells showed increased toxicity toward the epithelial barrier of Caco-2 cells. Taken together, these results indicate that C. jejuni bEV secretion is part of a survival strategy that connects environmental adaptation with pathogenicity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/714464v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@17aa2aforg.highwire.dtl.DTLVardef@4eab9dorg.highwire.dtl.DTLVardef@e4fba8org.highwire.dtl.DTLVardef@146109a_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2026

DNA-triggered AIM2 condensation orchestrates immune activation and regulation

The innate immune sensor AIM2 detects cytosolic DNA and initiates inflammatory responses, yet its activation mechanism remains incompletely understood. Here, we show that AIM2 undergoes liquid-liquid phase separation upon DNA binding, forming dynamic condensates both in vitro and in cells. These condensates serve as platforms for inflammasome and PANoptosome assembly, promoting immune activation across multiple pathways. Direct structural determination from condensates reveals the assembly of active-form ASC filaments. Mechanistically, liquid-phase condensation is governed by multivalent interactions involving different AIM2 domains, including previously uncharacterized regions and species-specific elements. In vitro and in vivo assays show that mutants specifically disrupting condensation impair immune complex assembly, cell death initiation, antimicrobial defense, and intestinal homeostasis. Moreover, AIM2-DNA condensates function as regulatory hubs targeted by host- and pathogen-derived factors to balance immune homeostasis or facilitate immune evasion. These findings establish liquid-phase condensation as a fundamental mechanism of AIM2 activation and a potential therapeutic target.

immunology↗

bioRxiv2026

The orbitofrontal cortex constructs allocentric schemas by integrating dynamic mobile agents with static environmental anchors

Scene construction involves the automatic synthesis of fragmented visual inputs into coherent mental models. While previous work has focused on static landscapes, real-world scenes require integrating dynamic agents with stable environmental anchors. We investigated the neural hierarchy underlying this transformation using an automatic space-encoding task in a 3D virtual-reality environment and fMRI representational similarity analysis. Results revealed functional segregation across visual cortex: the superior lateral occipital cortex encoded the first-person perspective of mobile character layouts, whereas the lingual gyrus and occipital fusiform cortex represented environments specified by visible landmarks. The orbitofrontal cortex integrated these streams into an allocentric spatial schema, capturing relational geometry beyond the current visual field. Following encoding, these representations were expressed in the anterior hippocampus for self-localization. Together, the findings demonstrate an automatic hierarchical transformation in which the OFC serves as a central scaffold for constructing allocentric spatial frameworks underlying stable scene representation.

neuroscience↗

bioRxiv2026

Cell body clustering drives gap junction-mediated synchronous activity in command neurons

The nervous system contains densely packed cell bodies, yet the role of neuronal cell body position in circuit function is poorly understood. Here we show that four Drosophila Moonwalker Descending Neurons (MDNs), command neurons for backward locomotion, must maintain cell body contact to allow gap junction-dependent synchronous activity necessary to initiate backward walking. MDNs express the transcription factor Hunchback, which drives expression of the Lar cell adhesion molecule; Hunchback, Lar, and its ligand Dlp promote MDN cell body clustering and backward walking. When clustered, the gap junction protein Inx8 allows synchronous firing of MDNs, which is required to initiate backward walking. These findings reveal a previously unappreciated role for cell body clustering and synchronous firing in neural circuit function.

neuroscience↗

bioRxiv2026

Vagus Nerve Stimulation Ameliorates Epilepsy via a Gut Microbiota-Butyrate-Vagus Nerve-Brain Axis

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, yet its mechanism remains partially understood. Here, through an integrated clinical-translational approach, we demonstrate that VNS modulates the gut microbiome and alter the level of butyrate to reduce seizure susceptibility via vagus nerve-dependent signaling. In a longitudinal cohort of epilepsy patients, VNS enriched short-chain fatty acid-producing bacteria, including Akkermansia muciniphila, Prevotella, Alistipes, and Odoribacter. Among clinical responders, fecal butyrate levels decreased concomitantly with an increase in plasma butyrate concentrations. Fecal microbiota transplantation from post-VNS patients into mice reduced seizure severity and improved gut barrier integrity. In a murine model of epilepsy, VNS similarly increased the abundance of Akkermansia and plasma butyrate concentrations, decreased fecal butyrate levels, and abolished its antiseizure effects upon vagotomy. Either colonization with Akkermansia muciniphila or exogenous butyrate supplementation was sufficient to reduce seizures and anxiety-like behavior, effects that also required intact vagal signaling. Our findings define a microbiota-butyrate-vagal pathway essential for the therapeutic effects of VNS, highlighting the gut-brain axis as a target for epilepsy treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/707138v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@8243e6org.highwire.dtl.DTLVardef@37f0e6org.highwire.dtl.DTLVardef@a8b321org.highwire.dtl.DTLVardef@1887342_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIVagus nerve stimulation (VNS) remodels the gut microbiota and alter the level of butyrate. C_LIO_LIVNS enriches short-chain fatty acids-producing bacteria, specifically Akkermansia muciniphila, in both humans and mice. C_LIO_LITransplantation of VNS-conditioned microbiota confers seizure protection and restores gut barrier integrity. C_LIO_LIAkkermansia muciniphila or exogenous butyrate is sufficient to reduce seizures via a vagus nerve-dependent pathway. C_LI

neuroscience↗

bioRxiv2026

AI-driven discovery and engineering of human endogenous nanocage proteins for mRNA delivery

Safe and effective gene delivery remains a central challenge for therapeutic applications. While non-viral and viral vectors have enabled substantial progress, their reliance on non-human components often triggers immune responses, limiting their use in chronic treatments. Here, we developed DeepDelivery, an artificial intelligence-driven platform to repurpose human proteins for mRNA delivery. An unbiased screening of the human proteome nominated 512 candidates, with experimental validation confirming that 80% of top-ranked hits form mRNA-encapsulating particles and mediate efficient functional delivery in human cells without provoking detectable inflammation. Notably, multiple tripartite motif (TRIM) family proteins, typically linked to antiviral responses, exhibited strong assembly and delivery activity. Quantitative analysis and interpretation of the model revealed structural domains that govern nanocage formation, enabling domain-guided engineering of TRIM25 variants with enhanced function. Our work establishes a generalizable framework for discovering human-derived delivery vehicles and provides a path toward programmable, non-immunogenic mRNA therapeutics.

synthetic biology↗

bioRxiv2026

PepMCP: A Graph-Based Membrane Contact Probability Predictor for Membrane-Lytic Antimicrobial Peptides

MotivationThe membrane-lytic mechanism of antimicrobial peptides (AMPs) is often overlooked during their in silico discovery process, largely due to the lack of a suitable metric for the membrane-binding propensity of peptides. Previously, we proposed a characteristic called membrane contact probability (MCP) and applied it to the identification of membrane proteins and membrane-lytic AMPs. However, previous MCP predictors were not trained on short peptides targeting bacterial membranes, which may result in unsatisfactory performance for peptide studies. ResultsIn this study, we present PepMCP, a peptide-tailored model for predicting MCP values of short peptides. We collected more than 500 membrane-lytic AMPs from the literature, conducted coarse-grained molecular dynamics (MD) simulations for these AMPs, and extracted their residue MCP labels from MD trajectories to train PepMCP. PepMCP employs the GraphSAGE framework to address this node regression task, encoding each peptide sequence as a graph with 4-hop edges. PepMCP achieved a Pearson correlation coefficient of 0. 883 and an RMSE of 0. 123 on th e node-level test set. It can recognize membrane-lytic AMPs with the predicted MCP values for each sequence, thereby facilitating mechanism-driven AMP discovery. Additionally, we provide a database, MemAMPdb, which includes the membrane-lytic AMPs, as well as the PepMCP web server for easy access. Availability and ImplementationThe code and data are available at https://github.com/ComputBiophys/PepMCP. Contactc.song@pku.edu.cn Supplementary InformationSupplementary data are available online.

bioinformatics↗