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Tracking flaviviral protease conformational dynamics by tuning single-molecule nanopore tweezers. 通过调整单分子纳米孔镊跟踪黄病毒蛋白酶构象动态
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-22 DOI: 10.1016/j.bpj.2024.11.017
Spencer A Shorkey, Yumeng Zhang, Jacqueline Sharp, Sophia Clingman, Ly Nguyen, Jianhan Chen, Min Chen

The flaviviral NS2B/NS3 protease is a conserved enzyme required for flavivirus replication. Its highly dynamic conformation poses major challenges but also offers opportunities for antiviral inhibition. Here, we established a nanopore tweezers-based platform to monitor NS2B/NS3 conformational dynamics in real time. Molecular simulations coupled with single-channel current recording measurements revealed that the protease could be captured in the middle of the ClyA nanopore lumen, stabilized mainly by dynamic electrostatic interactions. We designed a new Salmonella typhi ClyA nanopore with enhanced nanopore/protease interaction that can resolve the open and closed states at the single-molecule level for the first time. We demonstrated that the tailored ClyA could track the conformational transitions of the West Nile NS2B/NS3 protease and unravel the conformational energy landscape of various protease constructs through population and kinetic analysis. The new ClyA-protease platform paves a way to search for new allosteric inhibitors that target the NS2B and NS3 interface.

黄病毒 NS2B/NS3 蛋白酶是黄病毒复制所需的一种保守酶。它的高度动态构象带来了重大挑战,但也为抗病毒抑制提供了机会。在这里,我们建立了一个基于纳米孔镊的平台来实时监测 NS2B/NS3 的构象动态。分子模拟结合电生理学发现,蛋白酶可以被捕获在 ClyA 纳米孔腔的中间,主要通过动态静电相互作用来稳定。我们设计了一种新的伤寒沙门氏菌 ClyA 纳米孔,增强了纳米孔与蛋白酶的相互作用,首次在单分子水平上解析了打开和关闭状态。我们证明了定制的 ClyA 可以跟踪西尼罗河 NS2B/NS3 蛋白酶的构象转变,并通过种群和动力学分析揭示了各种蛋白酶构建体的构象能谱。新的 ClyA 蛋白酶平台为寻找针对 NS2B 和 NS3 界面的新型异构抑制剂铺平了道路。
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引用次数: 0
Structural dynamics of contractile injection systems. 收缩注射系统的结构动力学。
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-22 DOI: 10.1016/j.bpj.2024.11.019
Noah Toyonaga, L Mahadevan

The dynamics of many macromolecular machines are characterized by chemically mediated structural changes that achieve large-scale functional deployment through local rearrangements of constitutive protein subunits. Motivated by recent high-resolution structural microscopy of a particular class of such machines, contractile injection systems (CISs), we construct a coarse-grained semianalytical model that recapitulates the geometry and bistability of CISs in terms of a minimal set of measurable physical parameters. We use this model to predict the size, shape, and speed of a dynamical actuation front that underlies contraction. Scaling laws for the velocity and physical extension of the contraction front are consistent with our numerical simulations and may be generally applicable to related systems.

许多大分子机器的动力学特征是化学介导的结构变化,通过构成蛋白质亚单位的局部重排实现大规模功能部署。受最近对一类特殊的此类机器--收缩注射系统(CIS)--进行的高分辨率结构显微镜研究的启发,我们构建了一个粗粒度半分析模型,该模型通过一组最小的可测量物理参数再现了 CIS 的几何形状和双稳态力学。我们利用这一模型来预测作为收缩基础的动态驱动前沿的大小、形状和速度。收缩前沿的速度和物理延伸的缩放规律与我们的数值模拟一致,并可能普遍适用于相关系统。
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引用次数: 0
Physics of a super-fast viral jab. 超快速病毒注射的物理学原理
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-07 DOI: 10.1016/j.bpj.2024.11.006
Alex Mogilner
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引用次数: 0
Frequency-sensitive cell membrane dynamics under ultrasonic stimulation. 新的值得注意的:超声刺激下的频率敏感细胞膜动力学。
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-28 DOI: 10.1016/j.bpj.2024.11.3321
Bing Qi, Shaobao Liu
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引用次数: 0
Characteristic frequencies of localized stress relaxation in scaling-law rheology of living cells. 活细胞缩放律流变学中局部应力松弛的特征频率。
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-19 DOI: 10.1016/j.bpj.2024.11.015
Jiu-Tao Hang, Huajian Gao, Guang-Kui Xu

Living cells are known to exhibit power-law viscoelastic responses and localized stress relaxation behaviors in the frequency spectrum. However, the precise interplay between molecular-scale cytoskeletal dynamics and macroscale dynamical rheological responses remains elusive. Here, we propose a mechanism-based general theoretical model showing that cytoskeleton dissociation generates a peak in the loss modulus as a function of frequency, while the cytoplasmic viscosity promotes its recovery, producing a subsequent trough. We define two characteristic frequencies (ωc1 and ωc2) related to the dissociation rate of crosslinkers and the viscosity of the cytoplasm, where the loss modulus 1) exhibits peak and trough values for ωc1c2 and 2) monotonically increases with frequency for ωc1c2. Furthermore, the characteristic frequency ωc1 exhibits a biphasic stress-dependent behavior, with a local minimum at sufficiently high stress due to the stress-dependent dissociation rate. Moreover, the characteristic frequency ωc2 evolves with age, following a power-law relationship. The predictions of the dissociation-based multiscale theoretical mechanical model align well with experimental observations. Our model provides a comprehensive description of the dynamical viscoelastic behaviors of cells and cell-like materials.

众所周知,活细胞在频谱上表现出幂律粘弹性响应和局部应力松弛行为。然而,分子尺度的细胞骨架动力学与宏观尺度的动态流变响应之间的精确相互作用仍然难以捉摸。在此,我们提出了一个基于机理的一般理论模型,该模型表明细胞骨架解离会产生一个随频率变化的损失模量峰值,而细胞质粘度会促进其恢复,并产生一个随后的低谷。我们定义了与交联剂解离率和细胞质粘度有关的两个特征频率(ωc1 和 ωc2),其中损耗模量(1)在 ωc1>ωc2 时呈现峰值和谷值,(2)在 ωc1>ωc2 时随频率单调增加。此外,由于解离率与应力有关,特征频率 ωc1 表现出与应力有关的双相行为,在足够高的应力下出现局部最小值。此外,特征频率ωc2随着年龄的增长而变化,呈幂律关系。DMM 模型的预测结果与实验观测结果十分吻合。我们的模型全面描述了细胞和类细胞材料的动态粘弹性行为。
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引用次数: 0
A comprehensive method to analyze single-cell vibrations. 分析单细胞振动的综合方法
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-06 DOI: 10.1016/j.bpj.2024.11.003
Ali Al-Khaz'Aly, Salim Ghandorah, Jared J Topham, Nasir Osman, Taye Louie, Farshad Farshidfar, Matthias Amrein

All living cells vibrate depending on metabolism. It has been hypothesized that vibrations are unique for a given phenotype and thereby suitable to diagnose cancer type and stage and to pre-assess the effectiveness of pharmaceutical treatments in real time. However, cells exhibit highly variable vibrational signals, can be subject to environmental noise, and may be challenging to differentiate, having so far limited the phenomenon's applicability. Here, we combined the sensitive method of force spectroscopy using optical tweezers with comprehensive statistical analysis. After data acquisition, the signal was decomposed into its spectral components via fast Fourier transform. Peaks were parameterized and subjected to principal-component analysis to perform an unbiased multivariate statistical evaluation. This method, which we term cell vibrational profiling (CVP), systematically assesses cellular vibrations. To validate the CVP technique, we conducted experiments on five U251 glioblastoma cells, using 8- to 10-μm polystyrene beads as a control for comparison. We collected raw data using optical tweezers, segmenting into 150+ 5-s intervals. Each segment was converted into power spectra representing a frequency resolution of 10,000 Hz for both cells and controls. U251 glioblastoma cells exhibited significant vibrations at 402.6, 1254.6, 1909.0, 2169.4, and 3462.8 Hz (p < 0.0001). This method was further verified with principal-component analysis modeling, which revealed that, in cell-cell comparisons using the selected frequencies, overlap frequently occurred, and clustering was difficult to discern. In contrast, comparison between cell-bead models showed that clustering was easily distinguishable. Our paper establishes CVP as an unbiased, comprehensive technique to analyze cell vibrations. This technique effectively differentiates between cell types and evaluates cellular responses to therapeutic interventions. Notably, CVP is a versatile, cell-agnostic technique requiring minimal sample preparation and no labeling or external interference. By enabling definitive phenotypic assessments, CVP holds promise as a diagnostic tool and could significantly enhance the evaluation of pharmaceutical treatments.

所有活细胞都会随着新陈代谢而振动。有人假设,特定表型的振动是独一无二的,因此适用于实时诊断癌症类型、分期和预先评估药物治疗的效果。然而,细胞表现出的振动信号变化很大,可能会受到环境噪声的影响,而且可能难以区分,这些都限制了这一现象的适用性。在这里,我们将使用光学镊子(OT)进行力谱分析的灵敏方法与综合统计分析相结合。数据采集后,通过快速傅立叶变换(FFT)将信号分解为光谱成分。对峰值进行参数化并进行主成分分析(PCA),以执行无偏多变量统计评估。我们称这种方法为细胞振动谱分析(CVP),它能系统地评估细胞振动。为了验证 CVP 技术,我们在 5 个 U251 胶母细胞瘤(GBM)细胞上进行了实验,使用 8-10 μm 的聚苯乙烯珠作为对照进行比较。我们使用 OT 收集原始数据,将其分割为 150 多个五秒间隔。每个片段都被转换成功率谱(PS),代表细胞和对照组的频率分辨率均为 10,000 Hz。U251 GBM 细胞在 402.6、1254.6、1909.0、2169.4 和 3462.8 Hz 处表现出明显的振动(p
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引用次数: 0
Contact area and tissue growth dynamics shape synthetic juxtacrine signaling patterns. 接触面积和组织生长动态塑造了合成并列腺素信号模式。
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-15 DOI: 10.1016/j.bpj.2024.11.007
Jonathan E Dawson, Abby Bryant, Breana Walton, Simran Bhikot, Shawn Macon, Amber Ajamu-Johnson, Trevor Jordan, Paul D Langridge, Abdul N Malmi-Kakkada

Cell-cell communication through direct contact, or juxtacrine signaling, is important in development, disease, and many areas of physiology. Synthetic forms of juxtacrine signaling can be precisely controlled and operate orthogonally to native processes, making them a powerful reductionist tool with which to address fundamental questions in cell-cell communication in vivo. Here, we investigate how cell-cell contact length and tissue growth dynamics affect juxtacrine signal responses through implementing a custom synthetic gene circuit in Drosophila wing imaginal discs alongside mathematical modeling to determine synthetic Notch (synNotch) activation patterns. We find that the area of contact between cells largely determines the extent of synNotch activation, leading to the prediction that the shape of the interface between signal-sending and signal-receiving cells will impact the magnitude of the synNotch response. Notably, synNotch outputs form a graded spatial profile that extends several cell diameters from the signal source, providing evidence that the response to juxtacrine signals can persist in cells as they proliferate away from source cells, or that cells remain able to communicate directly over several cell diameters. Our model suggests that the former mechanism may be sufficient, since it predicts graded outputs without diffusion or long-range cell-cell communication. Overall, we identify that cell-cell contact area together with output synthesis and decay rates likely govern the pattern of synNotch outputs in both space and time during tissue growth, insights that may have broader implications for juxtacrine signaling in general.

通过直接接触进行的细胞-细胞通讯(或称共生信号传导)在发育、疾病和许多生理学领域都非常重要。合成形式的共生信号传导可以精确控制,并与原生过程正交运行,使其成为解决体内细胞通讯基本问题的强大还原工具。在这里,我们通过在果蝇翅膀显象盘中实施定制的合成基因回路,同时建立数学模型来确定合成诺奇(synNotch)激活模式,从而研究细胞-细胞接触长度和组织生长动力学如何影响并列信号反应。我们发现细胞之间的接触面积在很大程度上决定了同步诺奇激活的程度,从而预测信号发送细胞和信号接收细胞之间的界面形状将影响同步诺奇反应的大小。值得注意的是,突触诺奇的输出形成了一个分级空间轮廓,从信号源延伸出几个细胞直径,这提供了证据表明,当细胞增殖离开信号源细胞时,对并突触信号的反应可以在细胞中持续存在,或者说细胞仍然能够在几个细胞直径范围内直接交流。我们的模型表明,前一种机制可能就足够了,因为它预测了在没有扩散或长距离细胞间通信的情况下的分级输出。总之,我们发现细胞-细胞接触面积以及输出合成和衰减率可能会在组织生长过程中在空间和时间上控制 synNotch 的输出模式,这些见解可能会对一般的并列信号传导产生更广泛的影响。
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引用次数: 0
A physical model for M1-mediated influenza A virus assembly. M1 介导的甲型流感病毒组装物理模型。
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-11-20 DOI: 10.1016/j.bpj.2024.11.016
Julia Peukes, Serge Dmitrieff, François J Nédélec, John A G Briggs

Influenza A virus particles assemble at the plasma membrane of infected cells. During assembly all components of the virus come together in a coordinated manner to deform the membrane into a protrusion eventually forming a new, membrane-enveloped virus. Here, we integrate recent molecular insights of this process, particularly concerning the structure of the matrix protein 1 (M1), within a theoretical framework describing the mechanics of virus assembly. Our model describes M1 polymerization and membrane protrusion formation, explaining why it is efficient for M1 to form long strands assembling into helices in filamentous virions. Eventually, we find how the architecture of M1 helices is controlled by physical properties of viral proteins and the host cell membrane. Finally, by considering the growth force and speed of viral filaments, we propose that the helical geometry of M1 strands might have evolved to optimize for fast and efficient virus assembly and growth.

甲型流感病毒颗粒在受感染细胞的质膜上组装。在组装过程中,病毒的所有成分以一种协调的方式聚集在一起,使膜变形突起,最终形成一种新的膜包膜病毒。在此,我们将最近对这一过程的分子认识,特别是对基质蛋白 1(M1)结构的认识,整合到描述病毒组装力学的理论框架中。我们的模型描述了 M1 的聚合和膜突起的形成,解释了为什么 M1 能有效地形成长链,在丝状病毒中组装成螺旋状。最后,我们发现 M1 螺旋的结构是如何受病毒蛋白质和宿主细胞膜的物理特性控制的。最后,通过考虑病毒丝的生长力和速度,我们提出 M1 螺旋的几何形状可能是为了优化病毒快速高效的组装和生长而进化而来的。
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引用次数: 0
Vibrational signatures of living cells. 活细胞的振动特征。
IF 3.2 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-07 Epub Date: 2024-12-10 DOI: 10.1016/j.bpj.2024.12.008
Oren Tchaicheeyan, Ramon Zaera Polo, Beth Mortimer, Ayelet Lesman
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引用次数: 0
Tension makes the cell throw up
IF 3.4 3区 生物学 Q2 BIOPHYSICS Pub Date : 2025-01-03 DOI: 10.1016/j.bpj.2024.12.033
Hugo Lachuer
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引用次数: 0
期刊
Biophysical journal
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