Biophysical journal最新文献

{"title":"Effects of a cancer-associated mutation and multiple serine phosphorylation on poly(ADP-ribose) polymerase 2.","authors":"Bridget Hughes, Shubham Chatterjee, Mozhdeh Ghafari, G Andrés Cisneros","doi":"10.1016/j.bpj.2025.07.025","DOIUrl":"10.1016/j.bpj.2025.07.025","url":null,"abstract":"<p><p>Poly(ADP-ribose) polymerase 2 (PARP2) plays a crucial role in DNA repair. A common single-nucleotide polymorphism (SNP) in the PARP2 gene, rs3093921, has been associated with pancreatic cancer and marginal zone lymphoma. This SNP results in a missense mutation, D235G, in the PARP2 protein. PARP2 is also reported to undergo posttranslational modifications (PTMs), particularly phosphorylation at serine residues 226, 232, and 353. The C-terminal region of PARP2 includes the Trp-Gly-Arg (WGR) domain, the ADP-ribosyl transferase (ART) domain, and the helical subdomain (HD). The latter two, spanning residues 220-583, comprise the catalytic region of PARP2. The DNA-induced enzymatic activation of PARP2 is regulated by local destabilization of the HD domain. We used molecular dynamics simulations to investigate the impact of these three PTMs on both the wild-type (WT) and the mutant (D235G) forms of PARP2. Our simulations suggest that the mutation leads to a change in structure and residual flexibility in specific regions of the HD domain compared with the WT. The presence of the PTMs also shows altered structure of the HD domain, although the residual flexibility remains unchanged compared with the unmodified WT. This is further supported by the destabilizing interactions between the mutation site and the HD domain observed in the presence of both the mutation and the PTMs. Importantly, our results suggest that the three PTMs mitigate the changes in structure and residual flexibility caused by the mutation, helping the PTM-modified mutant protein retain WT-like features. We observe that, while the PTMs alter the dominant mode of motion in the native protein, this shift is not observed in the mutant, further indicating that PTMs mitigate the structural and dynamic consequences of the mutation, preserving WT-like behavior. The mutation and PTMs cause notable changes in correlated motions within the WGR and ART domains, with the PTM-modified mutant structure showing the strongest correlations. Interestingly, a similar trend is observed for anticorrelated motions, particularly between the WGR and ART domains, where the PTM-modified mutant structure again exhibits the highest level of anticorrelation. Additionally the mutation in PARP2 markedly weakens interdomain interactions between the HD and ART domains, as well as between the HD and WGR domains. By contrast, the PTMs alone show no change on the HD-ART interaction, although they weaken the HD-WGR interaction. For the PTM-modified mutant structure the HD-ART interaction remains disrupted compared with the WT, but the extent of disruption is less than that caused by the mutation alone-suggesting a partial compensatory effect of the PTMs. Additionally, the HD-WGR interaction remains consistently weakened in all modified systems.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5003-5012"},"PeriodicalIF":3.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741070","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":"Contractile to extensile transitions and mechanical adaptability enabled by activity in cytoskeletal structures","authors":"Alexandra Lamtyugina,Deb Sankar Banerjee,Yuqing Qiu,Suriyanarayanan Vaikuntanathan","doi":"10.1016/j.bpj.2026.09.011","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.011","url":null,"abstract":"Cytoskeletal network architecture is crucial in determining emergent morphology and dynamics, particularly in processes like stress fiber nucleation, where cells respond to mechanical cues. However, a clear understanding of the connection between architecture, dynamics, and mechanical response remains lacking. In this study, we investigate how self-assembled cytoskeletal structures respond to external mechanical perturbations, focusing on filament and crosslinker mixtures in two dimensions. Using agent-based models complemented by coarse-grained thermodynamic analysis, we reveal how molecular motor activity enables cytoskeletal structures to robustly adapt to changing mechanical conditions. Our simulations demonstrate that under tensile forces, self-assembled active asters transform into bundle-like structures, reminiscent of de novo stress fiber formation in living cells, while pre-existing active bundles elongate further in a reproducible and regulated manner. In contrast, passive assemblies exhibit no such qualitative morphological reorganization, highlighting the critical role of activity in mechanical adaptation. We derive a simple relation approximating active stress as a function of average relative motor alignment, a measure of mesoscopic architecture, which allows us to predict changes in stress characteristics in response to mechanical perturbations with or without morphological reorganization. Our results demonstrate how mesoscopic architecture and motor activity work in tandem to enable robust morphological and mechanical adaptation in cytoskeletal structures, providing insight into cellular mechanosensing and stress fiber formation.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"17 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973291","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":"Nanoscale co-condensation and stretch resistance of FUS and DNA.","authors":"Weiqian Dong, Wen-Ting Chu, Erkang Wang, Jin Wang","doi":"10.1016/j.bpj.2026.02.012","DOIUrl":"10.1016/j.bpj.2026.02.012","url":null,"abstract":"<p><p>Protein-DNA co-condensates where protein and DNA condensates colocalize, formed through liquid-liquid phase separation, play critical roles in gene expression, cancer, and developmental defects. Recent experimental studies have revealed the impact of mechanical stress on these co-condensates, but their dynamic processes and microscopic structures remain poorly characterized. Using coarse-grained molecular dynamics simulations, we investigated the nanoscale natures of FUS and DNA co-condensation under DNA stretching. We show that FUS and DNA contribute differently to co-condensation. Phase separation and superhelical structures lead to lag during the stretching-induced disruption of co-condensates, where lag refers to a delayed structural response that persists for a period before transition. The influence of pulling force on co-condensation displays a step-like pattern, and increasing force can reduce superhelical levels. These findings elucidate the mechanisms underlying the response of FUS-DNA co-condensation to mechanical stress and provide new insights into their regulatory roles in biological processes.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5234-5242"},"PeriodicalIF":3.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197077","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":"Topological learning prediction of virus-like particle stoichiometry and stability.","authors":"Xiang Liu, Xuefei Huang, Guo-Wei Wei","doi":"10.1016/j.bpj.2025.10.013","DOIUrl":"10.1016/j.bpj.2025.10.013","url":null,"abstract":"<p><p>Understanding the stoichiometry and associated stability of virus-like particles (VLPs) is crucial for optimizing their assembly efficiency and immunogenic properties, which are essential for advancing biotechnology, vaccine design, and drug delivery. However, current experimental methods for determining VLP stoichiometry are labor intensive and time-consuming. Machine learning approaches have hardly been applied to the study of VLPs. To address this challenge, we introduce a novel persistent-Laplacian-based machine learning mode that leverages both harmonic and nonharmonic spectra to capture intricate topological and geometric features of VLP structures. This approach achieves superior performance on the VLP200 data set compared with existing methods. To further assess robustness and generalizability, we collected a new data set, VLP706, containing 706 VLP samples with expanded stoichiometry diversity. Our persistent-Laplacian-based machine learning model maintains strong predictive accuracy on VLP706. Additionally, through random sequence perturbative mutation analysis, we found that 60-mers and 180-mers exhibit greater stability than 240-mers and 420-mers.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5027-5036"},"PeriodicalIF":3.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12558535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285563","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":"Endogenous and Exogenous Actin Modifications Alter F-Actin Network Architecture and Mechanics by Charge Redistribution","authors":"Peter Nietmann,Susanne Stenz,Kevin Kaub,Andrejus Suchenko,Mohan K. Balasubramanian,Andreas Janshoff","doi":"10.1016/j.bpj.2026.09.013","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.013","url":null,"abstract":"Mammalian actin comprises six highly conserved isoforms that, despite their near-identical amino acid sequences, form filament networks with remarkably diverse structural and viscoelastic properties. This diversity primarily originates from minor variations at the protein N-termini. To investigate the mechanisms driving these differences, we used microrheology to examine β -actin networks with modified N-termini. We focused on the effects of surface-charge alterations, which can occur naturally in cells or be introduced artificially via fluorescent labelling. Specifically, we studied post-translationally arginylated β -actin (Arg-actin), where multiple negative N-terminal charges are replaced by positive ones alongside naturally occurring intermediate variants. Our findings reveal that N-terminal charges act as localized filament-bundling agents, altering structural and viscoelastic properties in a manner distinct from traditional cross-linkers or chelators such as divalent cations. By intrinsically reducing the filament’s net negative surface charge, Arg-actin lowers the thermodynamic threshold for Manning counter-ion condensation. Consequently, Mg2+ drives premature, localized bundling at significantly lower concentrations, shifting the network from a purely entangled state to a nonlinear, stiffened architecture. Beyond advancing our understanding of cellular network mechanics, this study highlights critical implications for the use of fluorescent probes and other experimental protein modifications, demonstrating that such alterations can inadvertently shift network properties by orders of magnitude.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"12 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148964337","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":"Subdomains of endophilin can drive membrane remodeling and facilitate controlled membrane scission.","authors":"Jeriann R Beiter, Feng-Ching Tsai, Patricia Bassereau, Gregory A Voth","doi":"10.1016/j.bpj.2026.05.003","DOIUrl":"10.1016/j.bpj.2026.05.003","url":null,"abstract":"<p><p>The NBAR-domain-containing protein endophilin, a major player in many endocytic pathways, has offered considerable insight into Bin/amphiphysin/Rvs (BAR)-domain-driven membrane remodeling. However, understanding how the different subdomains of endophilin interact and how they sense and generate negative Gaussian curvature remains an unanswered question, with significant implications for the mechanisms and regulation of unconventional endocytic pathways. Using coarse-grained molecular dynamics simulation, we demonstrate the synergistic remodeling capabilities of the NBAR remodeling unit, as well as its ability to sort to and generate membrane regions with negative Gaussian curvature. We find that the assembly of NBAR scaffolds at regions of negative Gaussian curvature facilitates membrane hemifission in dynamic bud formation. These insights provide an additional role for endophilin scaffolds in endocytosis and emphasize the importance of developing new ways to study negative Gaussian curvature.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5375-5386"},"PeriodicalIF":3.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13215578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832944","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":"ProtLoc-GRPO: Cell line-specific subcellular localization prediction using a graph-based model and reinforcement learning.","authors":"Shuai Zeng, Weinan Zhang, Chaohan Li, Yuexu Jiang, Duolin Wang, Qing Shao, Dong Xu","doi":"10.1016/j.bpj.2026.02.001","DOIUrl":"10.1016/j.bpj.2026.02.001","url":null,"abstract":"<p><p>Subcellular localization prediction is crucial for understanding protein functions and cellular processes. Subcellular localization is dependent on tissue and cell lines derived from different cell types. Predicting cell line-specific subcellular localization using the information of protein-protein interactions (PPIs) offers deeper insights into dynamic cellular organization and molecular mechanisms. However, many existing PPI networks contain systematic errors that limit prediction accuracy. In this study, we propose a reinforcement learning approach, ProtLoc-GRPO, to enhance subcellular localization prediction by optimizing the structure of the underlying PPI network. ProtLoc-GRPO learns to rank and retain the most informative PPI edges to maximize the macro-F1 score for cell line-specific subcellular localization. Our approach yields a 7% improvement in macro-F1 score over the baseline. We further evaluate its robustness across various edge pruning rates and benchmark it against conventional pruning strategies. Results show that our proposed method consistently outperforms existing approaches. To our knowledge, this work represents the first sequence-based study to predict cell line-specific protein subcellular localization and the first application of the Group Relative Policy Optimization (GRPO) framework to a graph-based model for bioinformatics tasks.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5222-5233"},"PeriodicalIF":3.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123214","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":"Role of Hsp70 chaperone in client-protein folding elucidated by Markov state modeling and NMR restraint-assisted molecular dynamics simulations.","authors":"Michael S O'Connor, Kirill A Konovalov, Josephine L Duvall, Jinoh Jang, Yichong Lao, Silvia Cavagnero, Xuhui Huang","doi":"10.1016/j.bpj.2025.08.022","DOIUrl":"10.1016/j.bpj.2025.08.022","url":null,"abstract":"<p><p>Heat shock protein 70 (Hsp70) is a molecular chaperone that plays a key role in cellular processes by assisting protein folding and preventing aggregation. During client-protein folding, Hsp70 undergoes an ATP-dependent chaperone cycle involving the opening and closing of a flexible lid. Although the open-lid and closed-lid states of Hsp70 have been studied extensively, the specific role of the lid upon its interaction with client proteins remains unclear. In this study, we generated a Markov state model from coarse-grained molecular dynamics (MD) simulations of Hsp70 spanning from open-lid to closed-lid states and sampling a flexible lid-domain conformational ensemble. Starting from metastable Hsp70 conformations with varying degrees of lid opening, we performed nuclear magnetic resonance distance restraint-assisted all-atom MD simulations in explicit solvent to investigate the folding of the SH3 client protein bound to nucleotide-free Hsp70. All-atom MD simulations were performed with SH3 bound to and released from Hsp70, with nuclear magnetic resonance restraints applied to guide SH3 folding. Our results show that SH3 folds more effectively after having sampled conformational space within the closed-lid state of Hsp70. Further analysis reveals that the closed-lid state of Hsp70 interacts with SH3 via specific and highly conserved nonpolar residues, preventing the nonnative hydrophobic collapse of the SH3 client upon release from the chaperone. This study provides insights into specific atomic-level interactions that can be targeted by future experiments to better understand the molecular mechanism of Hsp70-assisted protein folding.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5013-5026"},"PeriodicalIF":3.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144941068","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":"Thermophoresis induced by photothermal shock alters reversal potential and capacitance in neurons.","authors":"Meisam Habibi Matin, Shulan Xiao, Krishna Jayant","doi":"10.1016/j.bpj.2026.04.031","DOIUrl":"10.1016/j.bpj.2026.04.031","url":null,"abstract":"<p><p>Laser-induced thermal shock is widely encountered in neuroscience and biology, yet its effects on cellular thermodynamics remain poorly understood. Using whole-cell patch-clamp recordings paired with two-photon laser stimulation, we reveal that photothermal shock causes a pronounced depolarizing shift in the potassium channel reversal potential in cortical neurons-a deviation from classical Nernstian predictions. We propose that thermophoresis-driven ion fluxes within intra- and extracellular spaces disrupt conventional thermodynamic equilibria, necessitating a revision of the traditional Nernst formulation for reversal potential. To validate this hypothesis, we integrate thermophoretic dynamics into a Poisson-Nernst-Planck model coupled with transient thermal diffusion. Our analysis demonstrates that although thermal gradients dissipate within sub-millisecond timescales, cellular relaxation persists much longer, imparting a residual thermal memory that governs ion redistribution-an effect overlooked by standard Hodgkin-Huxley and Goldman-Hodgkin-Katz models. This extended model accurately predicts the observed depolarizing shift in potassium reversal potential following photothermal shock. Furthermore, we show that the increase in membrane capacitance-often attributed solely to thermally induced membrane deformation-can also arise from thermophoresis-mediated ionic rearrangements. Together, these findings introduce a unified biophysical model for ionic transport under thermal gradients and establish a new theoretical foundation for the principled development of next-generation photothermal neurotechnologies.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5342-5359"},"PeriodicalIF":3.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147761211","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":"Conformational plasticity and sequence specificity interplay in non-canonical tandem RRM-RNA binding","authors":"Roxana Geanina Vasarhelyi,Vlad Cojocaru","doi":"10.1016/j.bpj.2026.09.015","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.09.015","url":null,"abstract":"The Dead End protein (DND1), a key regulator of germline cell fate, utilizes two RNA Recognition Motifs (RRM) in tandem to bind AU-rich RNA in a non-canonical manner. Only one RRM uses the known RNA binding interface, whereas the second motif has only minimal contacts with the RNA. To characterize the structural features and dynamics that contribute to RNA binding, we performed a series of atomistic molecular dynamics simulations and found that the complex is highly dynamic, deviating significantly from the experimental structure. We found that RNA binding restricts without abolishing the inter-domain motions of the RRMs and that cooperative binding of both RRMs is required to reduce the flexibility of the bound RNA. Through detailed analysis of the protein–RNA interactions, we show that the RNA binding interface in the tandem RRM–RNA complex remains stable despite extensive conformational plasticity. The RRMs cooperate to sustain a layered RNA binding mechanism, with aromatic stacking of the central adenosine with RRM1 residues as foundation, arginine residues anchoring the RNA backbone, and residues in the inter RRM linker forming hydrogen bonds with the RNA. Despite insufficient conformational space sampling to claim convergence, the protein-RNA interactions were consistent across multiple independent simulations with cognate and non-cognate RNA sequences. This substantiates our findings which showcase how structural dynamics impact RNA recognition, enabling structural adaptation for functional versatility in multi-domain proteins.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"126 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957858","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}