Biophysical journal最新文献

{"title":"A Biophysical Hypothesis for Compartment-Specific Conformational States of the IQSEC2 Intrinsically Disordered Protein","authors":"Michael Shokhen,Amnon Albeck,Nina S. Levy,Andrew P. Levy","doi":"10.1016/j.bpj.2026.09.007","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.007","url":null,"abstract":"The postsynaptic density (PSD) of neuronal synapses is a crowded, viscous membraneless compartment consisting of densely packed protein mixtures formed and maintained through liquid-liquid phase separation. A key regulator of synaptic function within the PSD is IQSEC2, an intrinsically disordered protein (IDP), which functions as a guanine nucleotide exchange factor (GEF), promoting the activation of the small GTPase ARF6 by catalyzing the exchange of ARF6 bound GDP for GTP. Experiments have shown that IQSEC2 is inactive in a folded state in the dendritic cytosol but can transiently adopt a catalytically active extended conformation in the PSD upon activation by neurotransmitter mediated calcium influx. In this study, we performed accelerated molecular dynamics (aMD) simulations of the IQSEC2 folding process in aqueous solvent and applied the Gibbs ergodic hypothesis formulated in statistical ensembles for post-processing and analysis of the results. We compared the effects of two sets of parameters on folding: a force field and a water model. The OPC water model optimized for proteins with disordered structure in the extended state in bulk aqueous solvent predicted an incorrect distorted 3D folded structure of IQSEC2. We propose that, due to fundamental biophysical differences between the dendritic cytosol and the postsynaptic density, there are two distinct classes of IDPs functioning in these different environments. These differences should be considered when optimizing force fields and parameters of water models for studying protein folding.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899107","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":"Revisiting the mode of action of daptomycin considering the inoculum effect and a novel liposome-MIC-competition assay","authors":"Sarah Crocoll,Lennard Forssmann,Luisa Munz,Georg Häcker,Andreas Bechthold,Heiko Heerklotz","doi":"10.1016/j.bpj.2026.09.004","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.004","url":null,"abstract":"Daptomycin (DAP) is a cyclic lipopeptide drug for intravenous application against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In spite of numerous studies, its mode of action remains controversial. This is partially due to the fact that no attention has been paid to the strong dependency of DAP activity on the cell count – referred to as the inoculum effect when minimal inhibitory concentrations (MICs) are concerned. The first objective is to quantify the inoculum effect of DAP acting against MRSA and, on this basis, review comparisons of data recorded at different cell counts. The data imply that the aqueous DAP concentration in equilibrium with minimally growth-inhibited MRSA is 0.24 μg/mL and the corresponding inhibitory drug load bound per bacterium is Rebac∗ = 1.0E+7. To directly compare phenomena observed at different cell counts, the samples must agree in Rebac∗; not in DAP concentration. The second objective has been to render data on liposomal model systems quantitatively comparable to in vivo data. This is achieved by the liposome-MIC-competition assay combining bacteria and liposomes in a single MIC experiment. It suggests an equivalent phosphatidylglycerol concentration of 3.5E-8 μM/(CFU/mL), giving rise to a re-assignment of model studies to comparable in vivo systems. Finally, the data obtained here are combined with common estimates regarding the lipid numbers per bacterium, suggesting that the majority of the bacteria-bound DAP is not localized in the membrane but most likely in the cell wall. Off-target binding is a crucial issue for membrane-active antibiotics.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"29 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899104","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.2026.08.024","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.08.024","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"24 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893393","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":"Mechanosensitive channels dominate the minimal ion channel repertoire in prokaryotes.","authors":"Cristóbal Uribe, Luciano Peña, Samuel Morales-Navarro, Sebastián E Brauchi, Gonzalo Riadi, Juan C Opazo, Wendy González","doi":"10.1016/j.bpj.2026.09.006","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.006","url":null,"abstract":"<p><p>The eukaryotic genomes encode hundreds of proteins that function as ion channels and transporters. Essential for sustaining life, these proteins mediate the movement of inorganic ions (e.g., K⁺, Na⁺, Cl^-, and Ca²⁺) across the plasma membrane according to their electrochemical gradients. In multicellular organisms, a diverse array of ion channels contributes to the maintenance of the resting membrane potential, the regulation of pH, osmolarity, and cell volume, and the control of secretion, electrical excitability, and synaptic activity, among many other fundamental physiological processes. Although independent evolutionary origins have been proposed for several ion channel families, their relative hierarchical importance for cellular viability remains poorly understood. To advance our knowledge of ion channel evolutionary history, we focused on determining the minimal combination of permeabilities that allows cellular viability. To this end, we conducted a survey of representative prokaryotes with small genomes across bacterial and archaeal phyla. By focusing on the smallest genomes, our approach enabled the identification of five ion channel architectures shared among prokaryotes. Among these, non-selective mechanosensitive channels (MscS and MscL) are the most abundant, followed by potassium channels, CLC-type channels and proton channels of the MotA/TolQ/ExbB family. The conservation of the mechanosensitive protein architecture across archaeal and bacterial membranes suggests that the capacity to monitor physical membrane integrity predates the requirements for electrical communication.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890865","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":"Hydrophobic mismatch induces lipid sorting based on tail unsaturation.","authors":"Niek van Hilten, Michael Grabe","doi":"10.1016/j.bpj.2026.09.003","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.003","url":null,"abstract":"<p><p>Biological membranes contain a diverse set of membrane proteins surrounded by many different lipids, and the lateral organization and function of these molecules are closely intertwined. Here, we use coarse-grained molecular dynamics (MD) simulations to explore how hydrophobic mismatch between the length of transmembrane (TM) proteins and the thickness of the surrounding lipid membrane impacts the spatial distribution of the lipids. We constructed idealized cylindrically symmetric proteins, inspired by the \"Mattress Model\" developed in the 1980's, and simulated these model proteins in different lipid compositions. We found that unsaturated lipids were attracted to short TM proteins that thinned the membrane, while fully saturated lipids were attracted to long TM proteins that induced membrane extension. A simple mechanical description of the membrane deformation energy coupled to a lipid mixing model accurately predicted the enrichment/depletion, which was up to 33% in some cases. Overall, we find that the main driver behind unsaturation-based sorting is the effective lipid length that conforms to match the hydrophobic thickness of the TM protein. Additionally, our simulations highlight that lipid sorting behavior is sensitive to protein tilt and protein surface roughness. By teasing out the fundamental physical principles in these simple models, our results provide a foundational understanding of how proteins and lipids form complex and transient assemblies, which we believe will be important for interpreting lipid-protein interactions for a host of membrane proteins that regulate cellular membranes and cell function.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890862","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":"Jie Liang (1964-2024): Introduction to modeling biology at multiple scales: From macromolecules to cells, dedicated to Jie Liang.","authors":"Ao Ma, Ruth Nussinov, Jianhan Chen, Jianhua Xing, Jie Xiao, Dong Xu, Meishan Lin, Pourya Delafrouz, Thomas Royston, Ke Tang, Bowei Ye, Jinfeng Zhang","doi":"10.1016/j.bpj.2026.08.015","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.08.015","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890887","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":"Low-Dimensional Energetic Landscape Governing Ca2⁺ Binding in Troponin C.","authors":"Abdul Basit","doi":"10.1016/j.bpj.2026.09.002","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.002","url":null,"abstract":"<p><p>Ca²⁺ binding regulates muscle contraction through coupled structural and dynamical mechanisms, yet a unified description of mutation-induced perturbations in binding energetics remains incomplete. Mutational effects on proteins are often high-dimensional and difficult to interpret mechanistically. Here, we develop a physically interpretable low-dimensional reaction coordinate that captures coordination environment, electrostatic features, and dynamical coupling. Structural, electrostatic, and dynamical descriptors correlate with experimental binding free energies with Pearson coefficients of Rp = 0.83, 0.83, and 0.85, respectively. Integration of these domains improves agreement with experiment (Rp = 0.90), indicating substantial dimensional compression of the underlying descriptor space. This framework provides a physically grounded description of how mutations reshape Ca2+ binding energetics in a minimal EF-hand system.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890931","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":"Hypoxia-Responsive HIF-1α-Dependent RhoA Signaling Promotes Motility and Aerotaxis in Polyaneuploid PC3 Cancer Cells with Increased Nuclear Rounding.","authors":"Noreen Hosny, Shengkai Li, Robert A Gatenby, Kenneth J Pienta, Joel S Brown, Emma U Hammarlund, Chen Yu, Junle Qu, Robert H Austin, Sarah R Amend","doi":"10.1016/j.bpj.2026.09.001","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.001","url":null,"abstract":"<p><p>Most cancer deaths result from metastasis, yet only a subset of tumor cells can complete this process. Polyaneuploid cancer cells (PACCs), which arise via endoreplication under stressors such as hypoxia, are implicated as metastatic drivers, but how they acquire this capacity remains unclear. Here, we show that under extreme self-generated hypoxia, the polyaneuploid subset of PC3 prostate cancer cells upregulates a hypoxia-responsive, HIF-1α-dependent RhoA signaling axis that promotes aerotaxis, a behavior predictive of intravasation during metastasis. We observe an enrichment of PACCs using a membrane-based culture system in which extreme, self-generated radial oxygen gradients emerge as cellular oxygen demand exceeds supply, recapitulating key features of the tumor microenvironment. Under these conditions, PACCs exhibited elevated HIF-1α and RhoA expression relative to non-PACCs. Disruption of either HIF-1α or RhoA attenuates aerotaxis, with RhoA expression suppressed upon HIF-1α inhibition, suggesting a functional HIF-1α- dependent RhoA pathway selectively enhanced in the PACC state. Quantitative analysis of nuclear morphology further reveals that nuclear circularity and solidity, morphology metrics associated with nuclear rounding and boundary organization, increase with and saturate at high nuclear area. Notably, the hypoxic PACC population exhibits significantly greater nuclear circularity and solidity compared to non-PACCs, suggesting increased rounding and stabilization of the enlarged nuclear architecture characteristic of PACCs under extreme hypoxia. Together, these findings reveal a new functional role for HIF-1α- dependent RhoA signaling in regulating aerotaxis in polyaneuploid cancer cells, which may enable aerotactic escape from hypoxic tumor cores and entry into oxygen-rich vasculature. Additionally, the association between elevated RhoA signaling and increased nuclear circularity at larger nuclear area suggests a potential link between hypoxia-responsive migration and maintenance of enlarged nuclear architecture in the PACC state. Collectively, these characteristics highlight PACCs as a hypoxia-adapted subpopulation with relevance for anti-metastatic therapeutic strategies.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886346","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":"Dimerization and Ligand Binding Rewire Allosteric Networks in SARS-CoV-2 Main Protease","authors":"Javier Sanlley Hernandez,Carla Calvó-Tusell,Fiona Kearns,Mac Kevin E. Braza,Rommie E. Amaro","doi":"10.1016/j.bpj.2026.08.023","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.08.023","url":null,"abstract":"The SARS-CoV-2 main protease (MPro) is an essential enzyme for viral replication and a primary target for antiviral drug development. Despite extensive structural and biochemical characterization, the allosteric mechanisms by which dimerization informs conformational changes at active site lack an explicit comparison across the different states that identify key residues that connect substrate binding, dimerization, and catalytic activation. Here, we integrate microsecond time scale all-atom molecular dynamics (MD) simulations with dynamical network analysis to characterize how ligand binding and dimerization modulate the allosteric communication landscape of MPro. We performed triplicate 1-μs simulations of MPro in the monomer and dimer states. For each of these states, we simulated MPro in the apo state, as well as bound to a natural peptide substrate (nsp 15/16), the covalent inhibitor nirmatrelvir (Paxlovid) and the noncovalent inhibitor ensitrelvir (Xocova). Dynamical network analyses from the resulting simulations reveal that dimerization redirects the highest correlated motions from the interdomain loop towards the domain II and III interface. At the dimer interface, we identified N-terminal and domain II β-hairpin residues that act as central communication hubs creating networks that connect both chains in the dimer. Small molecule binding to the active site further modulates these networks in distinct ways: nirmatrelvir and peptide substrate binding results in the formation of allosteric networks within the oxyanion loop, while ensitrelvir-bound monomeric MPro results in a dimer-like network, suggesting an inhibitory “allosteric switch” mechanism that may hinder dimerization upon binding. Across all systems, domain III emerges as an allosteric “pivot”, providing a platform that allows the most relevant networks to connect inter-chain communication to the active site upon dimerization. Together, these findings define how correlated motion networks couple active-site dynamics to dimerization and ligand binding, providing molecular insight into the principles governing allosteric regulation in MPro. This framework highlights potential avenues for developing antivirals that target not only the catalytic site but also the communication pathways sustaining dimer stability and enzymatic function.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"47 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877400","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":"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}