Cellular environments are crowded systems with reduced solvent polarity, yet how solvent polarity shapes RNA elasticity remains unclear. In this work, our high-precision magnetic tweezers and all-atom molecular dynamics simulations showed that decreasing solvent polarity with ethanol as a model cosolvent produces a biphasic response for double-stranded (ds) RNA: moderate ethanol concentration softens dsRNA, causing a slight decrease in bending persistence length P and stretch modulus S, but high ethanol concentration markedly stiffens dsRNA, reflected by the ∼2-fold increase in P and ∼4-fold increase in S. Furthermore, the twist-stretch coupling of dsRNA is strikingly reversed by ethanol of high concentration. The transition originates from the ethanol-enhanced ion neutralization giving way to major-groove clamping by monovalent ions as solvent polarity decreases. Further MD simulations mimicking reduced water polarity by scaling atomic charges reproduce these effects, establishing solvent polarity control maybe as a general mechanism for dsRNA in cells and a guiding principle for RNA-based nanostructure design.
{"title":"Low-polar solvent strikingly stiffens double-stranded RNA and reverses its twist-stretch coupling","authors":"Chen-Chen Zheng, Yun-Long Chen, Hai-Long Dong, Liang Dai, Xing-Hua Zhang, Zhi-Jie Tan","doi":"10.1016/j.bpj.2025.12.040","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.12.040","url":null,"abstract":"Cellular environments are crowded systems with reduced solvent polarity, yet how solvent polarity shapes RNA elasticity remains unclear. In this work, our high-precision magnetic tweezers and all-atom molecular dynamics simulations showed that decreasing solvent polarity with ethanol as a model cosolvent produces a biphasic response for double-stranded (ds) RNA: moderate ethanol concentration softens dsRNA, causing a slight decrease in bending persistence length P and stretch modulus S, but high ethanol concentration markedly stiffens dsRNA, reflected by the ∼2-fold increase in P and ∼4-fold increase in S. Furthermore, the twist-stretch coupling of dsRNA is strikingly reversed by ethanol of high concentration. The transition originates from the ethanol-enhanced ion neutralization giving way to major-groove clamping by monovalent ions as solvent polarity decreases. Further MD simulations mimicking reduced water polarity by scaling atomic charges reproduce these effects, establishing solvent polarity control maybe as a general mechanism for dsRNA in cells and a guiding principle for RNA-based nanostructure design.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"43 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894423","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}
Pub Date : 2026-01-02DOI: 10.1016/j.bpj.2025.12.026
Jieling Zhao, Jie Liang
Focal adhesions play critical roles in a variety of cellular behaviors and physiological processes, including cell migration, proliferation, wound healing, and tumor invasion. While focal adhesions are recognized as key protein signaling and mechanosensory hubs that mediate interactions between the cell and the extracellular matrix (ECM), the mechanisms by which cells sense and respond to ECM geometry at the subcellular level, and how these cues are translated into cell-scale behaviors, remain unclear. In this study, we develop a computational cell model to investigate the effects of adhesion pattern of 2D substrate on cell morphology and migration. The model has several advancements over existing approaches, including the incorporation of cellular viscoelasticity, dynamic cell-substrate communication, and a mechano-chemical feedback loop between cell adhesion and protrusion. The simulation results are directly compared with the experimental data and show remarkable agreement. Based on both simulations and validated experiments involving cells on substrate with directional patterns under Y-27632 and sh-βPix treatments, we propose that line tension along the cell boundary, driven by contractility, plays a dominant role in driving directed cell migration. Additionally, focal adhesion-mediated protrusion through chemical signaling supplement to maintain the migration directionality. These findings provide useful insights into the underlying mechanism of the effects of cell-ECM regulated mechano-chemical interactions on cell morphology and migration.
{"title":"Effects of adhesion pattern of 2D substrate on cell morphology and migration","authors":"Jieling Zhao, Jie Liang","doi":"10.1016/j.bpj.2025.12.026","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.12.026","url":null,"abstract":"Focal adhesions play critical roles in a variety of cellular behaviors and physiological processes, including cell migration, proliferation, wound healing, and tumor invasion. While focal adhesions are recognized as key protein signaling and mechanosensory hubs that mediate interactions between the cell and the extracellular matrix (ECM), the mechanisms by which cells sense and respond to ECM geometry at the subcellular level, and how these cues are translated into cell-scale behaviors, remain unclear. In this study, we develop a computational cell model to investigate the effects of adhesion pattern of 2D substrate on cell morphology and migration. The model has several advancements over existing approaches, including the incorporation of cellular viscoelasticity, dynamic cell-substrate communication, and a mechano-chemical feedback loop between cell adhesion and protrusion. The simulation results are directly compared with the experimental data and show remarkable agreement. Based on both simulations and validated experiments involving cells on substrate with directional patterns under Y-27632 and sh-βPix treatments, we propose that line tension along the cell boundary, driven by contractility, plays a dominant role in driving directed cell migration. Additionally, focal adhesion-mediated protrusion through chemical signaling supplement to maintain the migration directionality. These findings provide useful insights into the underlying mechanism of the effects of cell-ECM regulated mechano-chemical interactions on cell morphology and migration.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"33 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894424","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}
Pub Date : 2025-12-30DOI: 10.1016/j.bpj.2025.12.029
Seunghyun Ryu, Hasaeam Cho, Jimin Lee, Juncheol Lee, Byungsoo Kim, Sang Yeop Lee, Shina Min, Gyuheon Lee, Youli Li, Stuart C Feinstein, Cyrus R Safinya, Myung Chul Choi
Microtubules (MTs) are a major component of the eukaryotic cytoskeleton. MT architecture is highly regulated by MT-associated proteins such as Tau as well as a number of MT-targeted chemotherapeutic agents such as paclitaxel (PTX). In this study, we examined the ability of each of the six different alternatively spliced isoforms of human wild-type (WT) Tau (4R2N, 4R1N, 4R0N, 3R2N, 3R1N, and 3R0N) and PTX to bind to MTs as well as their effects upon MT structure. MTs were assembled in the physiologically relevant experimental regime of mixing WT Tau protein with unpolymerized tubulin and then treating the resulting MTs with PTX (i.e., Tau-coassembled MTs). The extent of Tau and PTX binding to MTs was assayed by co-sedimentation/Western blotting and high-performance liquid chromatography, respectively. Radial size of MTs was determined by synchrotron small-angle x-ray scattering. We observed that 4R Tau and PTX compete for binding to MTs, whereas 3R Tau and PTX exhibit only limited competition. These observations suggest that both 4R and 3R Tau bind initially to the well-studied binding sites on the outer surface of MTs, followed by binding to the less-well-understood binding site within the MT lumen in an isoform-specific manner. These binding events also lead to distinct effects on MT radial structure compared with MTs formed by PTX and then treated with Tau (i.e., PTX-stabilized MTs). Specifically, the inner radius of MTs first increased and then markedly decreased with increasing Tau concentrations. In addition to providing fundamental insights in the basic biochemistry of MTs, our results have implications regarding the onset and progression of chemotherapy-induced peripheral neuropathy, a consequence of many MT-targeted anticancer therapeutics including PTX. The differential use of the luminal Tau binding site in 4R versus 3R further raises the possibility of differential Tau isoform action in fetal versus adult nervous systems.
微管是真核细胞骨架的主要组成部分。MT结构受到微管相关蛋白（MAPs）如Tau以及许多MT靶向化疗药物（如紫杉醇（PTX））的高度调控。在这项研究中，我们检测了人类野生型（WT） Tau （4R2N、4R1N、4R0N、3R2N、3R1N和3R0N）和PTX的六种不同的可选剪接异构体与MT结合的能力以及它们对MT结构的影响。将WT Tau蛋白与未聚合的微管蛋白混合，然后用PTX处理产生的mt（即Tau共组装的mt），在生理学相关的实验制度下组装mt。分别采用共沉淀/western blotting和高效液相色谱法检测Tau和PTX与mt的结合程度。用同步加速器小角x射线散射（SAXS）测定了MTs的径向尺寸。我们观察到4R Tau和PTX在与mt结合时竞争，而3R Tau和PTX只表现出有限的竞争。这些观察结果表明，4R和3R Tau蛋白最初都与MT外表面上已被充分研究的结合位点结合，然后以一种异构体特异性的方式与MT管腔内不太为人所知的结合位点结合。与PTX形成的MT（即PTX稳定的MT）相比，这些结合事件对MT径向结构的影响也明显。具体来说，随着Tau浓度的增加，MTs的内半径先增加后显著降低。除了提供mt基本生物化学的基本见解外，我们的研究结果对化疗诱导的周围神经病变（CIPN）的发生和进展也有影响，这是许多mt靶向抗癌治疗的结果，包括PTX。4R和3R中管腔Tau结合位点的不同使用进一步提高了胎儿和成人神经系统中Tau同种异构体作用差异的可能性。
{"title":"Regulation of microtubule radial structure by competition between Tau and paclitaxel: Binding and x-ray scattering studies.","authors":"Seunghyun Ryu, Hasaeam Cho, Jimin Lee, Juncheol Lee, Byungsoo Kim, Sang Yeop Lee, Shina Min, Gyuheon Lee, Youli Li, Stuart C Feinstein, Cyrus R Safinya, Myung Chul Choi","doi":"10.1016/j.bpj.2025.12.029","DOIUrl":"10.1016/j.bpj.2025.12.029","url":null,"abstract":"<p><p>Microtubules (MTs) are a major component of the eukaryotic cytoskeleton. MT architecture is highly regulated by MT-associated proteins such as Tau as well as a number of MT-targeted chemotherapeutic agents such as paclitaxel (PTX). In this study, we examined the ability of each of the six different alternatively spliced isoforms of human wild-type (WT) Tau (4R2N, 4R1N, 4R0N, 3R2N, 3R1N, and 3R0N) and PTX to bind to MTs as well as their effects upon MT structure. MTs were assembled in the physiologically relevant experimental regime of mixing WT Tau protein with unpolymerized tubulin and then treating the resulting MTs with PTX (i.e., Tau-coassembled MTs). The extent of Tau and PTX binding to MTs was assayed by co-sedimentation/Western blotting and high-performance liquid chromatography, respectively. Radial size of MTs was determined by synchrotron small-angle x-ray scattering. We observed that 4R Tau and PTX compete for binding to MTs, whereas 3R Tau and PTX exhibit only limited competition. These observations suggest that both 4R and 3R Tau bind initially to the well-studied binding sites on the outer surface of MTs, followed by binding to the less-well-understood binding site within the MT lumen in an isoform-specific manner. These binding events also lead to distinct effects on MT radial structure compared with MTs formed by PTX and then treated with Tau (i.e., PTX-stabilized MTs). Specifically, the inner radius of MTs first increased and then markedly decreased with increasing Tau concentrations. In addition to providing fundamental insights in the basic biochemistry of MTs, our results have implications regarding the onset and progression of chemotherapy-induced peripheral neuropathy, a consequence of many MT-targeted anticancer therapeutics including PTX. The differential use of the luminal Tau binding site in 4R versus 3R further raises the possibility of differential Tau isoform action in fetal versus adult nervous systems.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861882","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}
Pub Date : 2025-12-26DOI: 10.1016/j.bpj.2025.12.031
Deepesh Sigdel, Maria Mills
{"title":"Molecular dynamics simulations reveal DNA gate opening mechanisms for M. smegmatis topoisomerase 1A","authors":"Deepesh Sigdel, Maria Mills","doi":"10.1016/j.bpj.2025.12.031","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.12.031","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"56 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145845497","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}
Pub Date : 2025-12-24DOI: 10.1016/j.bpj.2025.12.032
Alexandra A. Yakusheva, Andrei D. Megalinskii, Catherine Bourdon, Anita Eckly, Alexey M. Shibeko, Fazoil I. Ataullakhanov, Dmitry Y. Nechipurenko, Pierre H. Mangin, Mikhail A. Panteleev
{"title":"Transient build-up of a mural thrombus promotes intrathrombus coagulation reactions","authors":"Alexandra A. Yakusheva, Andrei D. Megalinskii, Catherine Bourdon, Anita Eckly, Alexey M. Shibeko, Fazoil I. Ataullakhanov, Dmitry Y. Nechipurenko, Pierre H. Mangin, Mikhail A. Panteleev","doi":"10.1016/j.bpj.2025.12.032","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.12.032","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"11 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145823745","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}
Pub Date : 2025-12-24DOI: 10.1016/j.bpj.2025.12.028
Stefanie D. Pritzl, Jan Lipfert
{"title":"Protein force spectroscopy using magnetic tweezers: slow and steady wins the race?","authors":"Stefanie D. Pritzl, Jan Lipfert","doi":"10.1016/j.bpj.2025.12.028","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.12.028","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"9 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822989","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}
Pub Date : 2025-12-23DOI: 10.1016/j.bpj.2025.12.024
Ramon Mendoza Uriarte, Benoît Roux
{"title":"Conductance of a potassium channel in the limit of zero membrane potential","authors":"Ramon Mendoza Uriarte, Benoît Roux","doi":"10.1016/j.bpj.2025.12.024","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.12.024","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822991","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}
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