Biophysical journal最新文献

{"title":"Electrostatics and disease: Large-scale assessment of human missense variants causing protein charge alterations and their implications for disease.","authors":"Nirav Modha, Shailesh Kumar Panday, Emil Alexov","doi":"10.1016/j.bpj.2026.07.023","DOIUrl":"10.1016/j.bpj.2026.07.023","url":null,"abstract":"<p><p>How do changes in electrical charge drive protein dysfunction and result in pathogenicity? This study investigates the relationship between charge-altering missense mutations and pathogenicity across a large-scale dataset, the Monogenic Genetic Disorder (MOGEDO) database. Using electrostatic energy calculations, we quantified the shift in interaction energy between the rest of the protein and either the wild-type or mutant residues. Our analysis shows that pathogenic variants are characterized by substantially larger electrostatic perturbations than their benign counterparts. We found that the outcome of a mutation is highly transition specific: because protein interiors tend to maintain a negative electrostatic potential, the introduction of acidic residues creates a destabilizing \"energy penalty.\" Conversely, basic residues often result in stabilizing shifts. Structural context further shaped these effects: buried residues showed larger electrostatic perturbation values overall, and pathogenic variants were enriched at deeply buried sites, consistent with reduced solvent screening amplifying charge perturbations. Because electrostatic interactions contribute substantially to protein binding and molecular recognition, the enrichment of pathogenic variants among binding-associated proteins suggests that electrostatic perturbations may be especially relevant in disease-associated contexts. Complementary analyses showed that pathogenic variants occur at more rigid local sites and are more often located in high-confidence modeled regions and that pathogenic-only genes show stronger gene constraint. This work therefore provides an electrostatics-focused framework for interpreting how charge-altering missense variants disrupt local protein electrostatic environments and how these disruptions are linked to pathogenicity.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4778-4795"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanosensitive ion channels in immunity from biophysics to mechanomedicine.","authors":"Hangyu Zhang, Dexiang Jiang, Yimin Mou, Ling Zhong, Zhuo Zhou, Jingyu Wang, Guy M Genin, Panpan Hou, Xiangjun Peng","doi":"10.1016/j.bpj.2026.07.024","DOIUrl":"10.1016/j.bpj.2026.07.024","url":null,"abstract":"<p><p>Immune cells operate within a dynamic mechanical environment. Shear stress, matrix stiffness, membrane tension, and cellular traction continuously shape their fate and function. Mechanosensitive ion channels (MSICs) are the convergent molecular transducers of these forces. Five families dominate immune mechanotransduction: Piezo, TRPV4, K_2P/TREK, TMEM63/OSCA, and ENaC. Each converts mechanical input into Ca²⁺, K⁺, or Na⁺ fluxes that drive the transcriptional and effector programs governing immune cell behavior. Two organizing principles that have emerged from the past decade of work structure this review. First, MSICs act as mechanical immune checkpoints. Their gating state controls T cell, NK cell, and dendritic cell function in stiff tumor stroma. This parallels the chemical checkpoints exploited by current immunotherapies. Second, MSICs display context-dependent functional polarity. The same channel produces opposite outputs depending on the magnitude, geometry, and timescale of the mechanical input. PIEZO1 has been reported to promote T cell activation under physiological shear in some experimental settings but restrain cytotoxicity in stiff stroma in others. It drives a pro-inflammatory macrophage phenotype in atherosclerosis but a tissue-reparative phenotype in sepsis. It restrains ILC2s acutely but drives type 2 pathology chronically. We integrate these principles with the structural biophysics of MSIC gating, contrasting force-from-lipid and force-from-filament mechanisms. We then trace MSIC function across macrophages, microglia, T cells, NK cells, dendritic cells, neutrophils, B cells, and innate lymphoid cells. We connect this biology to the emerging mechanomedicine toolkit: sonogenetics, magnetogenetics, force-responsive nanoparticles, organ-on-chip platforms, and engineered cellular therapies. Together, mechanical immune checkpoints and context-dependent polarity reframe immunity as a force-programmable system. This view positions MSICs as translational substrates for next-generation immunotherapies in cancer, autoimmunity, fibrosis, and chronic inflammation.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4541-4571"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148598565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coupling between sterol and sphingolipid structure in ordered membrane domains.","authors":"Israel Juarez-Contreras, Hyesoo Kim, Itay Budin","doi":"10.1016/j.bpj.2026.07.026","DOIUrl":"10.1016/j.bpj.2026.07.026","url":null,"abstract":"<p><p>A hallmark of eukaryotic membranes is the pairing of lineage-specific sterols with characteristic sphingolipid species. Mammalian cell membranes are enriched in both cholesterol and long-chain sphingolipids such as sphingomyelin, whereas fungi synthesize ergosterol and very-long-chain sphingolipids with sugar-containing head groups. It has been proposed that these two lipid classes co-evolved to support membrane structure and organization. Here, we investigated how sterol structure and sphingolipid chain length together control membrane order and phase behavior. In the yeast Saccharomyces cerevisiae, loss of very-long-chain C26 sphingolipids disrupted formation of liquid-ordered (L_o) domains in the vacuole membrane. Similarly, replacing ergosterol synthesis with that of cholesterol also prevented vacuole L_o domains from forming. To determine a possible physical basis of these effects, we investigated synthetic membranes of defined composition containing either ergosterol or cholesterol and sphingomyelin with different chain lengths. In membranes containing egg sphingomyelin with C16 chains, ergosterol only sparsely supported L_o domains, in contrast to cholesterol. Membranes containing sphingomyelin with C26 chains displayed a different pattern. Cholesterol mixtures were largely homogeneous across most compositions, with only a limited region that supported fluid domains. Ergosterol mixtures exhibited a distinct compositional window that supported fluid domains positioned between regimes of uniform membranes and gel phases. This window corresponded to lipidome changes in the vacuole as it phase separates during nutritional restriction. Measurements of membrane order showed that cholesterol strongly increased membrane packing compared to ergosterol in membranes containing egg sphingomyelin, whereas this difference was lost in membranes containing C26 sphingomyelin. The results suggest that sphingolipid chain length can tune sterol interactions needed for membrane organization.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4796-4808"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Actin filament assembly driven by distributive polymerases clustered on membrane surfaces.","authors":"R Dyche Mullins, Jane Kondev, Kristen Skruber","doi":"10.1016/j.bpj.2026.07.027","DOIUrl":"10.1016/j.bpj.2026.07.027","url":null,"abstract":"<p><p>Actin filaments created by the Arp2/3 complex form branched networks that grow and push against cellular membranes. We employ theory and simulation to describe how membrane surfaces accelerate filament assembly via clustering of proteins, including WAVE-family nucleation-promoting factors, that bind actin monomers and/or profilin-actin complexes. Briefly, thermal fluctuations drive filament tips on constrained, two-dimensional random walks across the membrane, where they collide with actin-charged polymerases. At low soluble actin concentrations, filament elongation is limited by delivery of monomers to the membrane surface; at high actin concentrations, elongation depends on how quickly fluctuating filaments search the membrane. Using measured parameter values, we conclude that surface-mediated polymerization can outpace solution-mediated elongation, even at high actin concentrations (>100 μM). The finite time required for profilin dissociation decreases the advantage conferred by surface-associated polymerases but only in the absence of force. Load forces enhance the effect of surface polymerases, which can both accelerate elongation and increase the force required to stall filament assembly.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4809-4827"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical pre-stretch of extracellular matrix regulates podosome dynamics via contact stiffness.","authors":"Chenxia Zhao, Xiaopeng Fan, Ruihao Xue, Keshu Feng, Liu Wang, Ze Gong","doi":"10.1016/j.bpj.2026.06.012","DOIUrl":"10.1016/j.bpj.2026.06.012","url":null,"abstract":"<p><p>Podosomes are actin-rich protrusions in immune cells that function as mechanosensors, helping cells to probe the extracellular matrix (ECM). These structures exhibit spontaneous oscillations, driven by a balance between actin-driven protrusion and myosin-mediated contraction. While podosome responses to matrix stiffness are well studied, their behavior in mechanically pre-stretched ECMs-common in both physiological and pathological contexts-remains unclear. In this study, we developed a chemo-mechanical model that integrates intracellular force generation with contact mechanics at the podosome-ECM interface. This model introduces ECM pre-stretch as a global deformation, altering the local stress field and modulating the contact response at the interface. Our model captures podosome oscillations and stiffness-dependent changes in protrusion depth, as reported in previous studies. Our model shows that pre-stretch reduces protrusion depth and enhances oscillations, driven by increased contact stiffness at the podosome-ECM interface. This work establishes a theoretical framework for understanding how ECM pre-stretch regulates podosome mechanosensing, identifying contact stiffness as a key link between interfacial mechanics and podosome dynamics.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4572-4584"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of hot spot residues in the FusB:EF-G binding interface","authors":"Anastasija Kulik,Iain Manfield,Arnout P. Kalverda,Andrew Wilson,Jennifer H. Tomlinson","doi":"10.1016/j.bpj.2026.09.033","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.033","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"9 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149050307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-body fluctuation-induced forces between membrane proteins: Insights from mesoscale simulations.","authors":"Adrià Bravo Vidal, Weria Pezeshkian","doi":"10.1016/j.bpj.2026.07.015","DOIUrl":"10.1016/j.bpj.2026.07.015","url":null,"abstract":"<p><p>The spatial organization of membrane-associated proteins is essential for a wide range of cellular processes, including signal transduction, endocytosis, and cell adhesion. While protein clustering can be driven by direct short-range forces, indirect interactions mediated by the membrane itself, particularly those arising from thermal shape fluctuations, are potentially sufficient to drive clustering in the absence of direct binding. In this study, we investigate how fluctuation-induced interactions contribute to the lateral organization of membrane inclusions using mesoscale simulations. Our approach is based on dynamically triangulated surfaces and is parameterized by three mesoscale quantities that capture local membrane rigidification and curvature induction. We show that local membrane rigidification drives the nonrandom organization of membrane inclusions and, above a critical concentration threshold, induces a fully segregated state. This threshold depends strongly on the magnitude of the induced rigidification. We further demonstrate that membrane tension only weakly affects lateral organization away from the threshold but has a pronounced effect near it. Extending our analysis to spherical geometries, we obtain similar behavior relevant to experiments on small unilamellar vesicles. In mixed systems containing two types of stiff inclusions, we find that stiffer proteins act as nucleation centers for softer proteins. Finally, we show that protein-induced curvature, combined with fluctuation-mediated clustering, can drive membrane shape remodeling. Our results are consistent with previous findings while additionally extending the characterization across the full parameter space and to new conditions of direct biological relevance. Overall, our findings suggest that local suppression of membrane-shape fluctuations by proteins generates effective attractive forces capable of driving protein reorganization on membranes, with broad implications for cell biology and the design of membrane-associated nanoparticles.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4725-4739"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of competition between precursor and mature microRNAs on stochastic gene expression.","authors":"Raunak Adhikary, Dipjyoti Das","doi":"10.1016/j.bpj.2026.07.010","DOIUrl":"10.1016/j.bpj.2026.07.010","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are key post-transcriptional regulators, processed from precursor miRNAs (pre-miRNAs) into mature miRNAs through nuclear and cytoplasmic proteins. Recent evidence shows that pre-miRNAs and mature miRNAs can compete for the same target mRNAs, yet the impact of this miRNA maturation-driven competition on gene expression noise remains unknown. We address this in widespread feedback motifs where both pre-miRNAs and mature miRNAs degrade a protein's transcripts, and the protein itself either activates or represses miRNA transcription. Using a mathematical model, we show that miRNA maturation tunes the behavior of positive or negative feedback loops, which function as bistable switches or oscillators at the mean-field level, respectively. The relative degradation of mature versus pre-miRNAs and the mRNA-miRNA co-degradation rates can jointly modulate the parameter regions of bistability or oscillations. Moreover, for positive feedback, stochastic simulations reveal that bimodal mRNA distributions emerge near the saddle-node bifurcation boundaries, but not always within the bistable regions. Bimodal mRNA distributions also appear for negative feedback, but outside the region of limit cycles. Importantly, in both feedback types, such noise-induced bimodality emerges in regions where mean-field analysis predicts no bistability or limit cycles. These results demonstrate that noise-induced phenotypic variability cannot necessarily be linked to underlying deterministic bifurcations and elucidate how miRNA maturation shapes stochastic gene expression in regulatory motifs relevant to development and disease.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4682-4700"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meso-Soup: A community approach to building a computational description of the biological mesoscale.","authors":"Sarah Anne Harris, Gianluca Lattanzi, Angelo Rosa, Ralf Everaers, Garegin Papoian, Adria Vidal, Chelsea Brown, Tanniemola Liverpool, Aldo Pasos-Trejo, Mohsen Sadeghi, Syma Khalid, Arvind Ramanathan, Oliver Henrich, Lorna Dougan, Zachary Freyberg, Weria Pezeshkian, David Sept, Beatrice Geiger, Riccardo Beccaria, Paul Beales, Roberto Covino, Ryan Cocking, Matteo Castelli, Sumanta Kundu, Simone Aureli, Davide Breoni, Fabio Mazza, Costanza Paternoster, Jules Morand, Manuel Micheloni, Francesco Cordoni, Lea Beaules, Pieter van der Hoek, Pietro Sillano, Luis Enrique Coronas, Kush Coshic, Lorenzo Petrolli, Antonio Trovato, Mikko Karttunen, Alessio Bartocci, Giovanni Novi Inverardi, Francesco Carnovale","doi":"10.1016/j.bpj.2026.07.016","DOIUrl":"10.1016/j.bpj.2026.07.016","url":null,"abstract":"<p><p>Physics-based models of biomolecular systems that explicitly represent biomolecular structure and mechanics, such as atomistic molecular dynamics simulations, are well established because experimental data have been available to iteratively improve and validate models. Now, simulations of the biological mesoscale are growing in importance because of the improvements in experimental tools to visualize this regime. This includes techniques such as cryo-electron microscopy and tomography, microscopies that follow individual proteins in their cellular contexts, in situ scattering to follow the dynamic evolution of biomolecular assembly, and omics tools. Together, these approaches, alone and in combination, have revealed the importance of interactomes that bridge multiple scales. Here, we describe the theoretical, computational, and cultural challenges that need to be overcome to gain an understanding of the biological mesoscale and offer potential solutions. This commentary is the result of a joint CECAM/CCPBioSim discussion workshop on how the community should address the challenges of biomolecular simulations at the mesoscale, held in Trento, Italy, in the summer of 2024. The aim is to provide a broad overview of the tools and techniques relevant to the biological mesoscale and to signpost readers to more detailed discussions in the cited literature.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4528-4540"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148598585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycogen-dependent demixing of frog egg cytoplasm at increased crowding.","authors":"James F Pelletier, Christine M Field, Margaret Coughlin, Lillia Ryazanova, Matthew Sonnett, Martin Wühr, Timothy J Mitchison","doi":"10.1016/j.bpj.2026.07.014","DOIUrl":"10.1016/j.bpj.2026.07.014","url":null,"abstract":"<p><p>Crowding increases the tendency of macromolecules to aggregate and phase separate, and regulated crowding contributes to subcellular organization and stress response. To explore the effect of crowding in a well-characterized model cytoplasm, we developed methods to concentrate the macromolecule components of Xenopus egg extracts without changing small molecules. Egg cytoplasm contains a high concentration of glycogen that serves as an energy store for early development. When crowding was increased 1.4×, the egg cytoplasm demixed into two liquid phases of approximately equal volume, one of which was highly enriched in glycogen. Glycogen hydrolysis prevented and reversed demixing. Quantitative proteomics showed that the glycogen-rich phase was enriched in proteins that bind glycogen, participate in carbohydrate metabolism, or are part of very high-molecular-weight complexes. The glycogen-depleted phase was enriched in ribosomes, endoplasmic reticulum (ER), and mitochondria. Smaller soluble proteins were approximately equipartitioned. Glycogen is usually observed in aggregates in intact cells, and recent work suggested a role for phase separation in its localization. Our results show that glycogen particles can spontaneously demix and suggest that demixing may be regulated by crowding.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"4715-4724"},"PeriodicalIF":3.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}