Biology subjects

Wang, H.

Publications and source records attributed to Wang, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Indole-3-propionic acid nano-prodrugs sustain increased lymphoid exposure and alleviate experimental autoimmune arthritis

Chronic inflammatory diseases, including rheumatoid arthritis (RA), currently require sustained control of inflammation. Although long-acting therapies can reduce dosing frequency, those that rely on systemic immunosuppression may still compromise protective immunity. Microbiota-derived metabolites offer a complementary starting point for immune modulation through naturally occurring host-microbe signals. Indole-3-propionic acid (IPA), a gut microbial tryptophan metabolite naturally present in human circulation, has newly recognized immunoregulatory activity, yet its effects across disease contexts and its potential for therapeutic use remain incompletely defined. Here, we developed polymeric IPA nano-prodrugs (pIPANP) by conjugating IPA to a methacrylamide polymer through ester linkages and formulating the polymer into injectable nanoparticles. Following subcutaneous administration of fluorescently-labeled pIPANP, injection-site fluorescence remained detectable for at least 35 days, with labeled material detected in multiple lymph nodes. LC-MS/MS confirmed higher lymph-node IPA concentrations in mice treated with the pIPANPs compared to free IPA control at every sampled time point over 14 days. In collagen antibody-induced arthritis (CAIA), pIPANPs reduced clinical disease severity and paw swelling under both prophylaxis and therapeutic administration. pIPANP treatment increased the relative representation of CD11cCD103CD11b- cells with a conventional dendritic cell (cDC)1-associated phenotype and reduced costimulatory-marker frequencies in both CD11cCD103 and CD11cCD11b populations, most prominently in hock-draining lymph nodes. These changes were accompanied by increased PD-1 and IFN-{gamma} frequencies among CD4 and CD8 T cells. Fluorescent nanoparticle tracking showed preferential association with several myeloid populations, while single-cell profiling revealed divergent interferon-response signatures across splenic populations. These findings reveal arthritis-associated immunomodulatory activity of polymeric IPA and support its further development as a microbiome-inspired, long-acting approach to inflammatory arthritis.

bioengineering↗

bioRxiv2026

Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy

Understanding how soluble monomeric alpha-synuclein transitions into pathological alpha-synuclein (Lewy bodies) has remained a central challenge in neurodegeneration. Existing models, largely based on treating cells and animals with pre-formed alpha-synuclein fibrils cannot account for the emergence of the first inclusion without pre-existing seeds. Here, we combine in vitro reconstitutions, computational modeling and a minimal cellular system to show that phase separation of alpha-synuclein with an interacting scaffold can recapitulate Lewy body-like structures. An unbiased proteomics screen, live-cell imaging, correlative light-electron microscopy, and soft X-ray tomography show that Lewy body-like structures are associated with redistribution of actin and membrane-bound organelles, with mitochondria accumulating at their periphery in an actin-dependent manner. Structural analyses further indicate that alpha-synuclein condensates provide local environments in which the insoluble beta-sheets can form. Together, these findings support a seed-independent trajectory from soluble alpha-synuclein through condensation and progressive immobilization to Lewy body-like assemblies and, subsequently, insoluble beta-sheet fibrils. This framework offers a new mechanistic route for understanding the disease progression and promises to guide the design of innovative therapeutic interventions.

neuroscience↗

bioRxiv2026

Hidden grassland productivity from overlooked herbivore impacts

Grasslands cover approximately 40% of Earth's land surface and contribute substantially to terrestrial primary production. Despite widespread grazing, field estimates of grassland aboveground net primary productivity commonly overlook two grazing-related processes: biomass consumed by herbivores and post-grazing compensatory growth. The magnitude and direction of the resulting biases remain unclear. Here we quantified these biases using a 3-year yak grazing experiment on the Tibetan Plateau, a meta-analysis of 152 grazing experiments across China, and a global synthesis of 212 paired observations from 58 studies. Overlooking biomass consumed by herbivores consistently underestimated productivity by 34-51%. By contrast, overlooking grazing-induced compensation generated smaller but more variable biases, ranging from 29% underestimation to 19% overestimation, mainly reflecting contrasting compensatory responses under rotational versus continuous grazing. These findings show that overlooking grazing-mediated processes introduces substantial, process-dependent biases in grassland productivity estimates, underscoring the need to incorporate these processes into ecosystem and climate assessments.

ecology↗

bioRxiv2026

NIH's dedicated K23 trial pathway was associated with more K-trial leadership but no detectable gain in new trials

Research funders often train investigators by funding a project, expecting the experience to produce leaders of the next one. Delivering the funded project and leading new work are different outcomes. In 2018 the US National Institutes of Health (NIH) created a dedicated clinical trial pathway for its K23 mentored career development awards. Using registry records for 1,847 K23 awardees and a language-model measurement corrected against blinded human review, we compared awardees whose awarded plans proposed their own trial with those whose plans did not, before and after the change. The pathway was followed by more leadership of the award-supported trial (difference in differences, 13.7 percentage points; 95% confidence interval, 5.7 to 21.2) but no detectable gain in leadership of distinct new trials (-3.8; -14.4 to 6.9), including over seven years. The K-trial estimate exceeded the new-trial estimate by 17.4 points (5.3 to 29.7) under every measurement correction. The additional supported trials were registered with the awardee as principal investigator and started at rates similar to earlier ones, whereas whether more awardees led any trial depended on the correction. Because groups were defined by awarded plans, the design cannot fully separate changes in behaviour from changes in who was funded. A training pathway can raise delivery of the work it funds without a detectable increase in leadership of further trials. As NIH consolidates its career awards and ends K support for trial conduct, evaluations should measure both outcomes.

scientific communication and education↗

bioRxiv2026

ScreenDMT reveals metabolites replicably associated with sleep disorders across three human cohorts

The robust replication of scientific findings across independent studies is essential, yet it remains challenging in high-dimensional biological datasets. A critical aspect of true replication requires detecting not only the repeated presence but also the consistent direction of an effect. Traditional methods for evaluating replication often ignore effect directionality or lack adequate statistical power when adjusting for multiple comparisons. To address this, we extend the directional MaxP test (DMT) and our screening-integrated procedure, ScreenDMT, to evaluate directional replication across an arbitrary number of independent studies. We mathematically prove ScreenDMT's validity for an arbitrary number of studies when the studies' sample sizes grow unbounded. Through extensive simulation studies, we demonstrate that ScreenDMT effectively controls error rates, such as the false discovery rate (FDR), in finite sample sizes and yields higher statistical power than competing methods especially for three studies. We applied the extended ScreenDMT to untargeted blood metabolomics profiles across three diverse human cohorts - ARIC (N=1,337), MESA (N=1,874), and HCHS/SOL (N=6,180) - to discover replicable biomarkers for dichotomous insomnia, long sleep, short sleep, and excessive daytime sleepiness (EDS). We found low levels of cortisol to be replicably associated with EDS, and high levels of n-formylmethionine to be associated with long sleep. Furthermore, directional pathway analysis revealed that low levels of xanthine metabolites are replicably associated with insomnia. These convergent findings validate ScreenDMT as a powerful methodology for simultaneous multi-cohort replication and offer robust insights into the metabolic signatures underlying sleep disorders across diverse populations.

bioinformatics↗

bioRxiv2026

Cooperative IDR-folded domain interplay governs HP1α phase separation and underlies biphasic regulation by pathogenic poly-PR

HP1 undergoes liquid-liquid phase separation (LLPS), yet the prevailing model, which attributes condensation almost entirely to intrinsically disordered regions (IDRs), leaves the role of its folded domains unresolved. Using solution and solid-state NMR, we show that HP1 LLPS is instead governed by reciprocal interplay between IDRs and folded domains. Within the condensed phase, solid-state NMR reveals a dynamic hierarchy: the chromoshadow domain (CSD) assembles into polymorphic oligomers that form rigid cores, while the phosphorylation sites on the N-terminal extension (NTE) remain highly mobile, challenging their proposed role as stable multivalent hubs. Phosphorylation of the NTE instead promotes LLPS primarily by increasing local rigidity and releasing the NTE from the chromodomain (CD) to relieve autoinhibition, with electrostatic charge contributing secondarily. The C-terminal extension (CTE) suppresses phase separation through two routes: weakening the association between the hinge region (HR) and the CSD, and inhibiting interactions between CSD dimers. ALS-associated poly-PR targets this network at the NTE and exerts concentration-dependent biphasic regulation, promoting LLPS at low concentrations via multivalent bridging and dissolving condensates at high concentrations via saturation, a switch recapitulated in cells and in mouse brain. These findings reframe HP1 condensation from an IDR-driven process to one cooperatively governed by IDR-folded domain interplay.

biochemistry↗

bioRxiv2026

Funding deadlines act as a zeitgeber for science

Funders decide which science is paid for. Whether they also shape when it becomes public has been hard to test. Across 376,542 preprints on bioRxiv and medRxiv, the US share rose by 2.3 to 2.7 percentage points in the four weeks before due dates for the main research grant of the National Institutes of Health (NIH) and dropped on the date. About one in eleven US preprints in those weeks was attributable to the deadline, and fields that depend least on NIH rose least. Among 15,906 funded investigators, the share of preprints posted in the four weeks before their own deadline was 9% higher than in other four-month cycles, and these preprints resembled the later grant without being more highly cited. Repeated before every due date, this individual surge matches the national peak's timing within a week. NIH's application calendar, like its funding, shapes when US biomedical science becomes public.

scientific communication and education↗

bioRxiv2026

Allyl chloride respiration by Dehalobacter shapes the fate of 1,2,3-trichloropropane

The synthetic compound 1,2,3-trichloropropane (1,2,3-TCP) is a persistent groundwater contaminant and probable human carcinogen for which effective detoxification pathways remain limited. Under anoxic conditions, microbial transformation of 1,2,3-TCP typically stalls at the intermediate allyl chloride, preventing complete detoxification. Here, we report the enrichment and characterization of Dehalobacter restrictus strain XRTCP, a bacterium capable of coupling dichloroelimination of 1,2,3-TCP with subsequent hydrogenolysis of allyl chloride to propene. While dichloroelimination to allyl chloride has been previously observed, the ability to utilize allyl chloride as a respiratory electron acceptor represents a previously unrecognized metabolic capability. This transformation was linked to microbial growth, with cell densities increasing by up to 74-fold during 1,2,3-TCP reduction and 15.8-fold during allyl chloride transformation. Metagenomic and metaproteomic analyses revealed a diverse repertoire of reductive dehalogenases (RDases), with expression patterns that differed between 1,2,3-TCP and allyl chloride amendments. Notably, a tcpA-like RDase was expressed under both 1,2,3-TCP and allyl chloride conditions, while distinct RDases were preferentially expressed under each substrate, indicating functional specialization within the dechlorination pathway. Despite this metabolic capability, propene formation remained limited due to rapid abiotic transformation of allyl chloride, primarily via reactions with reduced sulfur species, highlighting a critical branching point between biotic and abiotic pathways. These findings demonstrate that allyl chloride can function as a growth-supporting respiratory electron acceptor. More broadly, this work reveals how interactions between microbial metabolism and geochemical processes govern contaminant fate, with implications for improving both monitored natural attenuation and engineered bioremediation strategies for chlorinated solvents.

microbiology↗

bioRxiv2026

Archetype analysis of multiplexed antibody imaging reveals interpretable morphological programs in optical pooled screens

High-content imaging-based screens with small molecule or genetic perturbations rely on rich optical phenotypes, yet how distinct subcellular markers contribute complementary biological information remains unclear. Here, we introduce CellMAPP, a multiplexed organelle imaging platform that uses optical pooled screens with iterative antibody staining to map cellular architecture under perturbation. Using 17 markers across 524 genetic perturbations in MCF-7 cells, we systematically examined how individual, and combinations of, markers capture diverse morphological responses. We find that markers provide complementary views of perturbation effects, with increased multiplexing improving signal and the breadth of hit recovery, although some phenotypes are better recovered from a subset of features rather than a full profile. Because non-molecular image-based profiles can be challenging to link with interpretable biology, we developed CHART (available at https://github.com/Genentech/CHART), an archetype analysis framework that identifies distinct reference morphological states for each marker and uses multimodal large language models (MLLMs) to automatically annotate them, connecting cellular images to recognizable organelle phenotypes. Integrating archetypes across multiple markers revealed modular morphological programs that describe coordinated organelle reorganization in response to perturbation. This framework identified regulators of defined organelle states such as micronuclei, nominated novel gene functions and revealed complex patterns of multi-organelle reposition. Together, optical profiling with MAPP and CHART provides an interpretable, scalable framework for image-based screens that sheds light on rules governing cellular structural reprogramming.

systems biology↗

bioRxiv2026

The cleaved C-terminal domain of GmERS1-1 modulates cell cycle via GmACR1

Ethylene signaling orchestrates plant development and stress adaptation, yet how post-translational modifications of its receptors coordinate growth regulation remains unresolved. Here, we uncover a proteolytic processing mechanism of the soybean ethylene receptor GmERS1-1 that directly gates cell cycle progression. The GmERS1-1 mutants exhibit elevated yield under field conditions, whereas overexpression suppresses growth and hypersensitizes plants to ethylene. Ethylene triggers nuclear translocation of C-terminal domain (GmERS1-1-CEND), which is indispensable for receptor function. Mechanistically, GmERS1-1-CEND scaffolds a trimeric complex with GmACR1 and GmCDK7, enforcing G2/M phase arrest, thereby decoupling cell division from canonical ethylene transcriptional responses. Strikingly, ethylene-induced cell cycle blockade during apple fruit maturation mirrors this pathway, suggesting deep conservation across angiosperms. Our work defines a receptor processing-dependent signaling axis that directly interlinks phytohormone perception with cell cycle control, proposing tunable targets (e.g., GmERS1-1 cleavage efficiency) for engineering crop architecture and productivity.

plant biology↗

bioRxiv2026

Triple-Omics Analysis Unveiled the Neuroprotective Mechanisms of Akkermansia muciniphila in an Environmental Exposure-Linked Mouse Model of Alzheimer's Disease

Cadmium (Cd) is an emerging environmental risk factor for cognitive decline and Alzheimer's disease, and few interventions limit its effects on the brain. Akkermansia muciniphila, a human gut commensal, is neuroprotective through mechanisms that remain unclear. Building on our finding that A. muciniphila prevented Cd-induced memory deficits without reducing brain Cd burden (Wang et al., 2026a), we tested whether it reprograms Cd-disrupted hippocampal RNA regulation. Male C57BL/6J mice received A. muciniphila (1x10^9 CFU, oral gavage, 5 days/week) before and throughout 9 weeks of 3 mg/L CdCl2 exposure; hippocampi were analyzed by RNA-seq, m6A epitranscriptomic profiling, and rMATS-based alternative-splicing analysis. Cd disrupted hippocampal neuropeptide signaling, neuronal excitability, and synaptic plasticity. Co-exposure with A. muciniphila reversed signatures enriched for Nrf2-centered cytoprotective signaling and opposed m6A and splicing changes across more than a thousand genes, largely without changes in total mRNA abundance. Restored events converged on machinery governing local translation, calcium-dependent plasticity, and synaptic transmission. Projected onto predicted protein structures, most introduced a premature termination codon predicted to trigger nonsense-mediated decay or edited short loop and linker segments rather than rebuilding folded domains, regulation largely invisible to gene-level expression analysis. Among these, paired events amplifying semaphorin-plexin signaling, an axis linked to oligodendrocyte injury and memory consolidation, were reversed. These findings identify restoration of hippocampal transcript fate and splice-isoform selection as a mechanism potentially underlying A. muciniphila-mediated protection against Cd neurotoxicity, and establish post-transcriptional RNA regulation as a gut-brain target for mitigating environmentally driven neurotoxicity.

pharmacology and toxicology↗

bioRxiv2026

Lineage tracing reveals asynchronous fate restriction in mouse embryos and stem cell-derived embryo models

How a flexible mammalian embryo gives rise to a reproducible body plan remains unclear, partly because cell lineages cannot be followed continuously in vivo. We combined DNA Typewriter lineage recording with tetraploid complementation to reconstruct high-resolution single-cell genealogies across mouse development and built FateVec, an analysis framework that infers fate-bias dynamics and lineage-associated transcriptional programs from reconstructed phylogenies. Loss of developmental potential proved progressive and asynchronous, with multiple lineages acquiring detectable fate bias before morphological diversification at gastrulation. Within the neural crest, most cells remained multipotent over an extended window, while independent founder clades differed markedly in restriction timing. Extending lineage recording to a stem-cell-derived embryo model revealed that cells with shared transcriptional identities can arise from distinct lineage relationships. We further found embryonic-lineage contributions to extraembryonic-like states, exposing an unexplored lineage plasticity. This lineage-resolved view of embryogenesis reveals that cell identity alone predicts neither developmental ancestry nor the timing of fate restriction.

developmental biology↗

bioRxiv2026

Functional characterization of terpene synthases from Dendrobium nobile provides insights into the biosynthesis of copaborneol, a proposed dendrobine precursor

Abstract: Picrotoxane-type sesquiterpene alkaloids, including dendrobine, are characteristic constituents of Dendrobium nobile, but the enzymes that produce their proposed skeletal precursors remain in completely characterized. Here, we combined tissue metabolite profiling with genome-guided screening and biochemical characterization of terpene synthases (TPSs). GC-MS analysis revealed variation in sesquiterpenoid profiles and dendrobine signals among tissues and developmental stages. Manual curation of the chromosome-level genome yielded 16 full-length TPS-a candidates. Functional screening in an FPP-supplying Escherichia coli system showed that three closely related genes on chromosome 1, DnTPS1~DnTPS3, produced copaborneol as their dominant product. The principal product of DnTPS1 was purified and identified by NMR spectroscopy, and a purified-enzyme assay confirmed its direct conversion of FPP to copaborneol. Fluorescence imaging in rice protoplasts and Nicotiana benthamiana leaves indicated predominantly cytosolic localization of DnTPS1. Guided by sequence comparisons and structural modeling, we tested 12 DnTPS1 variants and found that substitutions at W377 and I295 altered the relative distribution of sesquiterpene products. Phylogenetic and regional gene-order analyses placed DnTPS1~DnTPS3 in the same clade and identified related TPS candidates within corresponding genomic regions of six Dendrobium species. These findings establish that three D. nobile TPSs can form copaborneol and identify DnTPS1 residues that influence product selectivity, providing a basis for testing the proposed connection to dendrobine biosynthesis.

biochemistry↗

bioRxiv2026

The microbial soy metabolite S-equol mitigates cadmium neurotoxicity in mice

Environmental exposures are major but understudied determinants of chronic disease. Cadmium is a pervasive toxic metal encountered through diet and tobacco smoke that has been associated with cognitive impairment and Alzheimer's disease mortality, yet strategies to mitigate its neurotoxicity remain limited. S-equol is a gut microbial metabolite of soy daidzein that crosses the blood brain barrier and preferentially activates estrogen receptor beta. Here, we show that cadmium disrupts an axis linking the equol producing gut bacterium Adlercreutzia equolifaciens to circulating S-equol and hippocampal estrogen receptor expression in mice, that S-equol attenuates cadmium-induced cytotoxicity and restores neuronal, glutamatergic and synaptic transcriptional programs in mouse neural progenitor cells, and that circulating S-equol in older humans is lower in apolipoprotein E4 carriers and covaries with body mass index, identifying S-equol as a microbiome-derived, host-modulated candidate countermeasure against cadmium neurotoxicity.

neuroscience↗

bioRxiv2026

Patronin condensation integrates recognition, protection and organization of microtubule minus ends

Microtubule minus ends are central to non-centrosomal microtubule organization, yet how their recognition, protection and molecular organization are integrated remains unclear. Here we show that Drosophila Patronin forms dynamic condensates at microtubule minus ends through a prion-like domain (PrLD). PrLD-mediated condensation cooperates with the CKK domain and a second CKK-independent recognition region to convert weak or broadly distributed microtubule-binding activities into persistent minus-end recognition and tracking. Replacing the PrLD with a heterologous phase-separating HNRNPA1 IDR restores minus-end targeting, indicating that condensation capacity rather than PrLD primary sequence is critical. Patronin condensates further form a protective cap that resists minus-end depolymerization and recruit the cytoskeletal regulators Sas-4, Katanin and Ena. Disrupting PrLD multivalency impairs Patronin localization at multiple developmental sites and causes early organismal lethality. Thus, Patronin condensation creates a physiologically essential microtubule minus-end compartment coupling end recognition, stabilization and cytoskeletal organization.

cell biology↗

bioRxiv2026

Folate metabolism in tumor-associated macrophages drives immunosuppressive function to promote tumor growth

Tumor-associated macrophages (TAMs) promote tumor growth, inhibit effector lymphocytes, and induce resistance to immune checkpoint inhibitors (ICI). Therapies designed to deplete TAMs have had little success in the clinic, and strategies aimed to repolarize immunosuppressive TAMs to pro-inflammatory states have struggled with systemic toxicity. We have identified that the combination of low folate in the tumor microenvironment and TAM dependency on the high affinity folate receptor beta (FR{beta}) for folate uptake results in a unique metabolic dependency of TAMs necessary for their immunosuppressive function. FR{beta} (encoded by Folr2) is uniquely expressed on myeloid cells and upregulated on TAMs. FR{beta}+ TAMs exhibit an immunosuppressive phenotype in melanoma and are associated with worse clinical outcomes and resistance to ICI in melanoma patients. We generated a novel Folr2-/- mouse model to study why TAMs express a unique folate receptor and showed that tumor growth was slowed in the absence of Folr2 in a T-cell dependent manner. We observed a dramatic repolarization of Folr2-/- TAMs in vivo to pro-inflammatory states, resulting in increased cytotoxic T cell and NK cell infiltration into tumors. Importantly, we show that folate is low in the tumor microenvironment by performing metabolomics on melanoma tumors and adjacent normal tissue from warm autopsy patient specimens, and that we could increase tumor growth in Folr2-/- mice by increasing serum folate to supraphysiologic concentrations with a high folate diet. Integrated metabolomics and transcriptomic analysis demonstrated that Folr2-/- macrophages have impaired folate uptake and 1C metabolism-based reduction of oxidized glutathione in low folate conditions, resulting in increased mitochondrial reactive oxygen species (ROS) in Folr2-/- cells. Excess ROS results in leakage of mitochondrial DNA into the cytoplasm, activating cGAS-STING signaling and promoting pro-inflammatory macrophage polarization through TBK1 and NF-kB. Together, our data demonstrate that TAM expression of FR{beta} promotes their immunosuppressive functions by maintaining folate uptake in the low folate tumor microenvironment, suggesting that FR{beta} is a novel metabolic checkpoint on TAMs.

immunology↗

bioRxiv2026

Multi-omics fine-mapping uncovers a pleiotropic intestinal enhancer variant linking PMAIP1 regulation to pig growth and fatness

Genetic loci influencing multiple complex traits often remain difficult to interpret because the underlying functional variants, target genes and tissue contexts are unresolved. Here, we investigated the regulatory basis of a shared signal for average daily gain (ADG) and backfat thickness (BF) in Yorkshire pigs. By integrating GWAS in 7,972 pigs, targeted capture sequencing, LD-based fine-mapping, porcine epigenomic annotations, three-dimensional chromatin interaction maps and functional assays, we narrowed the shared SSC1 signal to a 1.59-Mb interval and functionally prioritized rs334769214 (T>G) as the leading candidate variant. The T>G substitution produced marked allele-specific differences in enhancer activity and nuclear-protein binding, while transcription-factor co-transfection assays identified FOXL1-responsive, allele-dependent regulatory activity. Chromatin interaction and CRISPRa analyses supported a regulatory connection between the rs334769214-containing enhancer and PMAIP1, and PMAIP1 overexpression promoted apoptosis in porcine intestinal epithelial cells. In the capture-sequenced subset, the G allele was associated with higher ADG and BF, consistent with a relative loss-of-activation model. Together, these findings delineate a candidate FOXL1-enhancer-PMAIP1 regulatory pathway and demonstrate how multi-omics fine-mapping can advance a shared quantitative-trait locus toward a testable molecular mechanism underlying variation in growth and fatness.

genetics↗

bioRxiv2026

Ultrafast and Accurate Selection of High-Quality Protein Complex Models from Large-Scale Prediction

In the post-AlphaFold era, advances in protein complex structure prediction have enabled the generation of thousands of candidate models per target, making the accurate and efficient selection of high-quality models from large candidate pools a critical challenge. Existing model-selection approaches commonly employ estimated model accuracy (EMA) methods, which include single-model and consensus-based methods. The former lack cross-model comparative information, whereas the latter often incur high computational costs from pairwise structural alignments and are influenced by candidate-pool quality. Here, we present DeepUMQA-Selection, a two-stage framework combining single-model accuracy estimators for preliminary selection with Ultrafast Shape Recognition (USR)-based structural alignment for consensus selection. Preliminary selection enriches the candidate pool with high-quality models and reduces subsequent structural comparisons, while USR-based structural alignment enables efficient consensus selection without explicit structural superposition. On the retrospective CASP16 QMODE3 benchmark dataset, DeepUMQA-Selection outperformed all participating methods and predictor-derived confidence metrics, as measured by mean Top-5 weighted penalty. The advantage was particularly pronounced for heteromeric targets, with a 13.9% improvement in model-selection performance relative to the best-performing CASP16 participating method. Furthermore, a confidence-assisted strategy enabled the framework to accommodate larger protein complexes while maintaining superior model-selection performance over competing methods, supporting its scalability. Runtime benchmarking showed that the proposed USR-based structural alignment achieved a substantial 317-fold speedup over US-align for candidate pools containing 1,000 models, demonstrating its computational efficiency for large-scale model selection. Our results demonstrate that DeepUMQA-Selection enables accurate and computationally efficient selection of high-quality protein complex models from large-scale candidate pools.

bioinformatics↗