Biophysical journal最新文献

{"title":"Computational modelling of toroidal membranes at division and fission sites","authors":"Chris L.B. Graham,Matyas Parrag,Phillip J. Stansfeld,Christopher D.A. Rodrigues","doi":"10.1016/j.bpj.2026.10.020","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.020","url":null,"abstract":"The formation of specialised membrane architectures is fundamental to biological processes. Computational modelling of membrane structures offers a means to unravel complex molecular mechanisms that remain inaccessible through in vitro or in vivo approaches. Among these architectures, toroidal membranes, otherwise known as fusion pores or fission pores, occur during the final stages of cell division, exocytosis, endocytosis, and membrane fission; including during the phagocytic-like engulfment of bacterial endospores. Here we have designed ‘MemTorMD’, a computational simulation pipeline based on the ‘Triangulated Surface to Coarse Grain’ (TS2CG) methodology, to enable coarse-grained modelling of free toroidal membranes with biologically relevant dimensions. This approach allowed us to overcome the hurdles and determine the lipid properties required for stable toroidal membrane formation, thus providing a biologically accurate simulation surface. Furthermore, we demonstrate the applicability of this approach to investigate the function of proteins that localise at toroidal membranes and drive molecular events such as membrane fission, by a prokaryotic fission protein. Collectively, our work using coarse grained molecular simulations provides insight into the simulation of biologically accurate toroidal membranes, as well as protein behaviour at toroidal membranes, and offers a computational platform for further development of more complex simulations involving additional molecular components at toroidal membranes present in a range of processes across life.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149230117","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":"Determinants of centromeric nucleosome conformation","authors":"Emeleeta A. Paintsil,Joshua Lee,Sarah S. Meidl Zahorodny,Jeff Wereszczynski,Emma A. Morrison","doi":"10.1016/j.bpj.2026.10.018","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.018","url":null,"abstract":"Centromeric chromatin is defined by the presence of the histone H3 variant CENP-A, which forms a specialized nucleosome required for kinetochore assembly. Compared to canonical H3 nucleosomes, CENP-A nucleosomes exhibit an open DNA conformation that leaves an additional 13 base pairs of DNA accessible at the entry and exit sites. While the CENP-A αN-helix has previously been implicated in promoting this enhanced DNA breathing, the contributions of the intrinsically disordered N-terminal tail and adjacent latch regions of CENP-A to nucleosome conformation remain unknown. The intrinsically disordered N-terminal regions of histone H3 are known to facilitate interactions with DNA to stabilize overall nucleosome conformation. Here, we utilized a combination of MNase digestion assays and coarse-grained molecular dynamics simulations of nucleosomes containing targeted swaps of the H3 and CENP-A tail, latch, and αN-helix regions to systematically test the contribution of each N-terminal histone region to nucleosomal DNA conformation. Substitution of individual H3 N-terminal regions with those of CENP-A opened the DNA at the entry/exit sites and increased DNA accessibility. While any single CENP-A N-terminal region was sufficient to open the canonical nucleosomal DNA conformation, replacement of any single CENP-A N-terminal region with its H3 counterpart was insufficient to restore the closed DNA conformation characteristic of canonical H3 nucleosomes. Instead, progressive incorporation of multiple H3-derived regions produced increasingly closed DNA conformations, demonstrating that the H3 tail, latch, and αN-helices act cooperatively to stabilize wrapped nucleosomal DNA. Taken together, these findings demonstrate that the more restricted DNA breathing of canonical nucleosomes arises from coordinated contributions across multiple N-terminal regions and suggest that the multi-region redundancy in the conformational flexibility of the centromeric nucleosome could emphasize the importance of retaining flexibility in the centromeric nucleosome, even upon post-translational modification and binding to structural proteins.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"291 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225919","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":"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, nonselective mechanosensitive channels (MscS and MscL) are the most abundant, followed by potassium channels, chloride (ClC) 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":"5792-5807"},"PeriodicalIF":3.7,"publicationDate":"2026-10-20","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":"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 1980s, 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 membrane deformation energy coupled to a lipid mixing model accurately predicted 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":"5755-5768"},"PeriodicalIF":3.7,"publicationDate":"2026-10-20","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":"In silico model of axonal pathfinding during spinal cord regeneration in zebrafish larvae","authors":"Oskar Neumann,Mathar Kravikass,Nora John,Rahul Gopalan Ramachandran,Paul Steinmann,Vasily Zaburdaev,Daniel Wehner,Silvia Budday","doi":"10.1016/j.bpj.2026.10.013","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.013","url":null,"abstract":"Functional spinal cord repair in zebrafish is governed by regeneration-favorable biochemical and mechanical cues within the lesion microenvironment. Alterations in extracellular matrix composition and stiffness are closely associated with axon regeneration and its failure. However, experimentally dissecting the interplay between mechanical signals and axonal regrowth in vivo remains technically challenging. Here, we present an agent-based modeling framework to simulate stiffness-mediated axonal growth trajectories across the lesion. We use this model to explore potential mechanisms underlying the characteristic growth patterns observed during zebrafish spinal cord regeneration. Experimental growth profiles of regenerated axons were averaged and compared with mean simulation profiles obtained using different mechanosensing parameter sets. Among the tested parameter combinations, a common parameter set yielded the highest profile overlap at 48 hours post lesion. These exploratory comparisons demonstrate that the model can generate selected features of the observed spatial signal distributions of regenerated axons. Hence, our computational framework provides an in silico platform for investigating the role of mechanical cues in axon regeneration in the injured zebrafish spinal cord.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"13 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221610","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":"Cosolvents induce sharp softening and RNA-like twist-stretch coupling of RNA-DNA hybrid","authors":"Chen-Chen Zheng,Yun-Long Chen,Zhe Wang,Liang Dai,Xing-Hua Zhang,Zhi-Jie Tan","doi":"10.1016/j.bpj.2026.10.014","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.014","url":null,"abstract":"Cellular environments generally contain abundant organic cosolvents, yet how in-cell cosolvents modulate the mechanics of RNA-DNA hybrid (RDH) duplex remains unclear. Here, we combined high-precision magnetic tweezer experiments with all-atom molecular dynamics simulations to investigate the structural elasticity of RDH duplexes using PEG200, PEG1000, and ethanol as model cosolvents. We found that high-concentration cosolvents sharply soften RDH duplexes in bending and induce an apparent RNA-like positive twist-stretch coupling. Specifically, for RDH duplex, the bending persistence length P decreases from ∼54 nm to ∼27-35 nm (∼35-50% decrease) by 40% cosolvents. Meanwhile, the twist-stretch coupling parameter dL/dN shifts from ∼0 to -0.56−-0.45 nm/turn, approaching that of RNA duplex (∼-0.81 nm/turn). Microscopic analyses revealed that sharp bend softening mainly arises from local hydrogen-bond disruption associated with structural mismatch between RNA and DNA strands and enhanced strand fluctuation driven by increased ion neutralization. Moreover, the RNA-like twist-stretch coupling originates from cosolvent-induced shifts of structure and deformation pathway of RDH duplex toward RNA-like ones from comprehensive analyses at the helix, base-pair, and strand levels. Our findings revealed that cosolvents can substantially reshape the structure and mechanics of RDH duplexes, potentially providing a physical basis for understanding their behavior in cells.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"11 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221460","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":"Characterizing the unfolding activation barrier of c-MYC G-quadruplex by temperature-dependent single-molecule force spectroscopy","authors":"Yingxian Qian,Yashuo Zhang,Hui Peng,Qun Luo,Huijuan You","doi":"10.1016/j.bpj.2026.10.015","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.015","url":null,"abstract":"Parallel-stranded G-quadruplexes (G4s) exhibit remarkable kinetic stability. However, it remains elusive whether this kinetic stability arises from an intrinsically high activation energy Ea or a constrained transition pathway. Here, we integrated an objective-based heating system with single-molecule magnetic tweezers to quantify the unfolding dynamics of c-MYC promoter G4s (MYC2345) from 16°C to 51°C. As the temperature increased, the peak unfolding force decreased from 58 ± 4 pN to 40 ± 4 pN, while the unfolding rate ku increased from (4.6 ± 0.1) × 10-8 s-1 to (1.4 ± 0.1) × 10-5 s-1. Arrhenius analysis yielded a moderate unfolding activation energy of 137 ± 19 kJ·mol-1 (∼55 kBT). Notably, this Arrhenius slope is markedly shallower than that of duplex DNA, demonstrating that G4 unfolding is less sensitive to thermal fluctuation than duplex melting. The kinetic stability of the c-MYC G4 is mainly due to the small transition distance rather than a high enthalpic barrier. Furthermore, the folding rate kf of G4 exhibits low temperature sensitivity, increasing 1.5-fold between 23°C and 37°C, suggesting that the folding kinetics are dominated by the entropic barrier. Our results provide a direct quantitative measurement of G4 energy landscapes.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"45 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221544","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":"Glycosaminoglycans Differentially Modulate Meniscus Pericellular Matrix Micromechanics and Mechanosensing","authors":"Chao Wang,Yuchen Liu,Mohammad Jafari,Mingyue Fan,X. Lucas Lu,Robert L. Mauck,Farid Alisafaei,Lin Han","doi":"10.1016/j.bpj.2026.10.012","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.012","url":null,"abstract":"In the meniscus, cells reside within a specialized pericellular matrix (PCM) microniche that exhibits distinct molecular and structural features compared to the surrounding fibrous extracellular matrix (ECM). The PCM is enriched in negatively charged sulfated glycosaminoglycans (sGAGs), primarily contributed by localized proteoglycans such as aggrecan. Using the murine meniscus as the model, this study delineates the specific contributions of sGAGs to the elastic and viscoelastic micromechanics of the PCM and explores their influence on resident cell mechanosensing. Enzymatic removal of sGAGs markedly decreases the PCM micromodulus and alters its viscoelastic properties, including faster relaxation time constants. Finite element modeling suggests that the localized fixed charges and mechanical buffering provided by sGAGs in the PCM serve as a protective mechanism for resident cells under tensile loading, the predominant loading mode of the meniscus outer zone in vivo. Nevertheless, despite these pronounced contributions to PCM micromechanics, sGAG depletion induces a modest reduction in intracellular calcium signaling ex vivo under hypertonic, but not isotonic or hypotonic, conditions. Collectively, these findings establish sGAGs as critical regulators of fibrocartilage PCM integrity and highlight their differential roles in local PCM micromechanics versus cell mechanosensing.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"14 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149209255","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":"Molecular clockwork hypothesis for the KaiABC circadian oscillations.","authors":"Masaki Sasai, Shin Fujishiro","doi":"10.1016/j.bpj.2026.10.008","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.008","url":null,"abstract":"<p><p>When three cyanobacterial proteins-KaiA, KaiB, and KaiC-are incubated with ATP in vitro, the phosphorylation level of KaiC exhibits stable circadian oscillations. Biochemical and structural analyses have shown that KaiC's ATPase activity is crucial for these oscillations, leading to the hypothesis that ATP-consuming dynamics function as a molecular clock, determining the oscillation period of individual molecules. Moreover, these molecular clocks synchronize collectively, resulting in oscillations at the ensemble level. In this study, we develop a theoretical model to test this molecular clockwork hypothesis. Our model clarifies the relationship between the oscillation period and ATPase activity, explaining the significant changes in the period induced by amino acid substitutions near the CI-CII domain boundary of the KaiC hexamer. Furthermore, the model addresses the physical basis for temperature compensation concerning both the oscillation period and ATPase activity. Thus, the molecular clockwork perspective provides a framework for understanding the atomic design behind collective oscillations.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206441","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":"Molecular mechanism of water and glycerol transport through hydrophobic selectivity filter in the aquaporin homolog of Trypanosoma brucei","authors":"Peerzada Maajid Parsa,Ramasubbu Sankararamakrishnan","doi":"10.1016/j.bpj.2026.10.011","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.011","url":null,"abstract":"The protozoan parasite Trypanosoma brucei is implicated in deadly African sleeping sickness. Experimental studies show that T. brucei codes for three aquaporin homologs (TbAQP1 to TbAQP3). TbAQP2 has been established as the high affinity drug transporter of drugs pentamidine and melarsoprol. Mutation in TbAQP2 or its loss results in pentamidine-melarsoprol cross-resistance. TbAQP2 is also shown to transport water, glycerol and other solutes to respond to osmoregulation in the infected hosts or glycerol metabolism. Experimentally determined structures of TbAQP2 show that it adopts the same aquaporin-like hourglass helical fold. However, the so called aromatic/arginine selectivity filter (Ar/R SF) in TbAQP2 has neither arginine nor aromatic residue and all four residues are hydrophobic. Mutation and functional studies have demonstrated the role of Ar/R SF residues in the transport and selectivity of solutes in aquaporin homologs. The intriguing question is how the completely hydrophobic Ar/R SF region enables the transport of water and glycerol molecules. In this study, we used computational approach to elucidate the molecular mechanism of water and glycerol transport. Our equilibrium molecular dynamics simulations showed that the number of water molecules transported by TbAQP2 is almost one order of magnitude higher than that of prototype water channel AQP1. Moreover, the residence time within TbAQP2 channel is much less compared to that found in AQP1. The relatively wider constriction, interactions of water molecules with the selectivity filter residues and the contact duration, all contribute to a large number of water molecules transported through TbAQP2 channel. Our umbrella sampling studies show that when glycerol is transported through TbAQP2, it participates in interactions with channel residues that can be considered as complimentary to that observed in prototype glycerol transporter GlpF. Our studies reveal the molecular mechanism of water and glycerol transport in TbAQP2 and establish that TbAQP2 is an efficient water transporter.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"11 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173043","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}