Biophysical journal最新文献

{"title":"Effects of molecular interaction and liver sinusoidal mechanical properties on leukocyte adhesions.","authors":"Jingchen Zhu, Shenbao Chen, Lüwen Zhou, Xiaobo Gong, Yuhong Cui, Yan Zhang, Mian Long, Shouqin Lü","doi":"10.1016/j.bpj.2024.11.3315","DOIUrl":"10.1016/j.bpj.2024.11.3315","url":null,"abstract":"<p><p>It is interesting to find pathologically that leukocytes, especially neutrophils, tend to adhere in the liver sinusoids dominantly but not in the postsinusoidal venules. While both views of receptor-ligand interactions and physical trapping are proposed for mediating leukocyte adhesion in liver sinusoids, integrated investigations for classifying their respective contributions are poorly presented. With a combination of Monte Carlo simulation and immersed boundary method, this study explored numerically the effects of molecular interaction kinetics and sinusoidal mechanical properties on leukocyte adhesion in liver sinusoid jointly. Results showed that, within the range of biological limitations, the lumen stenosis ratio, leukocyte stiffness, Disse space stiffness and endothelium permeability regulate the comprehensive adhesion process in a descending order of significance in the presence of receptor-ligand interactions. While leukocyte adhesions could be mutually promoted with proper combinations of leukocyte stiffness, lumen stenosis, and molecular interaction, the binding affinity is insensitive under the conditions with low leukocyte stiffness in normal lumen stenosis and high leukocyte stiffness in high lumen stenosis. This work deepens the understanding of recruitment mechanism of leukocyte in liver sinusoids.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"480-493"},"PeriodicalIF":3.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738149","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 Analyses of Molecular Force Sensors for Mechanical Characterization of Biological Systems.","authors":"Diana M Lopez, Carlos E Castro, Marcos Sotomayor","doi":"10.1016/j.bpj.2025.01.025","DOIUrl":"10.1016/j.bpj.2025.01.025","url":null,"abstract":"<p><p>Mechanical forces play key roles in biological processes such as cell migration and sensory perception. In recent years molecular force sensors have been developed as tools for in situ force measurements. Here we use all-atom steered molecular dynamics simulations to predict and study the relationship between design parameters and mechanical properties for three types of molecular force sensors commonly used in cellular biological research: two peptide- and one DNA-based. The peptide-based sensors consist of a pair of fluorescent proteins, which can undergo Förster resonance energy transfer (FRET), linked by spider silk (GPGGA)_n or synthetic (GGSGGS)_n disordered regions. The DNA-based sensor consists of two fluorophore-labeled strands of DNA that can be unzipped or sheared upon force application with a FRET signal as readout of dissociation. We simulated nine sensors, three of each kind. After equilibration, flexible peptide linkers of three different lengths were stretched by applying forces to their N- and C-terminal Cα atoms in opposite directions. Similarly, we equilibrated a DNA-based sensor and pulled on the phosphate atom of the terminal guanine of one strand and a selected phosphate atom on the other strand for pulling in the opposite direction. These simulations were performed at constant velocity (0.01 nm/ns - 10 nm/ns) and constant force (10 pN - 500 pN) for all versions of the sensors. Our results show how the force response of these sensors depends on their length, sequence, configuration and loading rate. Mechanistic insights gained from simulations analyses indicate that interpretation of experimental results should consider the influence of transient formation of secondary structure in peptide-based sensors and of overstretching in DNA-based sensors. These predictions can guide optimal fluorophore choice and facilitate the rational design of new sensors for use in protein, DNA, hybrid systems, and molecular devices.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188020","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":"Temperature Dependence of Membrane Viscosity of Ternary Lipid GUV with L_o Domains.","authors":"Julia Tanaka, Kenya Haga, Naohito Urakami, Masayuki Imai, Yuka Sakuma","doi":"10.1016/j.bpj.2025.01.024","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.01.024","url":null,"abstract":"<p><p>In the cell membrane, it is considered that saturated lipids and cholesterol organize liquid-ordered (L_o) domains in a sea of liquid-disordered (L_d) phase, and proteins relevant to cellular functions are localized in the L_o domains. Since the diffusion of transmembrane proteins is regulated by the membrane viscosity, we investigate the temperature dependence of the membrane viscosity of the ternary GUV composed of the saturated lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the unsaturated lipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol (CHOL) to understand the effect of the phase separation on the membrane viscosity using microinjection technique. In the microinjection method, membrane viscosity is estimated by comparing the flow pattern induced on a spherical membrane with a hydrodynamic model. For phase-separated GUVs, the flow pattern is visualized by the motion of the domains. In this study, we developed a method to visualize the flow patterns of homogeneous GUVs above the phase separation temperature by using beads attached to the GUVs. We succeed to measure the membrane viscosity of ternary GUVs both above phase separation temperature and in the phase-separated region and find that the membrane viscosity decreases dramatically by the phase separation. In the phase-separated region, i.e., GUV with L_o domains, the membrane viscosity is determined by that of the L_d phase, η_Ld, and show weak temperature dependence compared with that of the DOPC single component GUV, which is a main component of the L_d phase. We revealed that the Moelwyn-Hughest (MH) model which takes into account the effects of the membrane composition, viscosity of pure component and interaction between components well describes the obtained membrane viscosity of the ternary GUV both above phase separation temperature and in the phase-separated region. The drastic decrease of the membrane viscosity by the phase separation plays an important role in regulating the mobility of constituents in multi-component membranes.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188023","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":"Growth of Nonmotile Stress-Responsive Bacteria in Three-Dimensional Colonies under Confining Pressure.","authors":"Samaneh Rahbar, Farshid Mohammad-Rafiee, Ludger Santen, Reza Shaebani","doi":"10.1016/j.bpj.2025.01.021","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.01.021","url":null,"abstract":"<p><p>We numerically study three-dimensional colonies of nonmotile stress-responsive bacteria growing under confining isotropic pressure in a nutrient-rich environment. We develop a novel simulation method to demonstrate how imposing an external pressure leads to a denser aggregate and strengthens the mechanical interactions between bacteria. Unlike rigid confinements that prevent bacterial growth, confining pressure acts as a soft constraint and allows colony expansion with a nearly linear long-term population growth and colony size. Enhancing the mechanosensitivity reduces instantaneous bacterial growth rates and the overall colony size, though its impact is modest compared to pressure for our studied set of biologically relevant parameter values. The doubling time grows exponentially at low mechanosensitivity or pressure in our bacterial growth model. We provide an analytical estimate of the doubling time and develop a population dynamics model consistent with our simulations. Our findings align with previous experimental results for E. coli colonies under pressure. Understanding the growth dynamics of stress-responsive bacteria under mechanical stresses provides insight into their adaptive response to varying environmental conditions.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073627","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":"Positive Feedback between RyR Phosphorylation and Ca²⁺ Leak Promotes Heterogeneous Ca²⁺ Release in Cardiac Myocytes.","authors":"Daisuke Sato, Bardia Ghayoumi, Anna Fasoli, Christopher Y Ko, Donald M Bers","doi":"10.1016/j.bpj.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.01.023","url":null,"abstract":"<p><p>Structural heterogeneity in the distribution of ryanodine receptor (RyR) clusters in cardiac myocytes has been shown to have pro-arrhythmic effects. The presence of a mixture of large and small RyR clusters can potentiate arrhythmogenic calcium (Ca²⁺) waves. RyRs are subject to post-translational modifications (PTMs), such as phosphorylation, which are linked to heart failure and other pathological conditions. This study aims to investigate how PTMs interact with the structural heterogeneity of RyR clusters and further increase heterogeneous Ca²⁺ release activities in cardiac myocytes. Using a physiologically detailed 3-dimensional ventricular myocyte model containing approximately two million stochastic RyR channels, we simulated heterogeneous distributions of RyR clusters with and without PTMs. The results demonstrate that Ca²⁺ cycling and RyR phosphorylation by Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) create a positive feedback loop, which increases functional heterogeneity in the Ca²⁺ spark size distribution. In large clusters, Ca²⁺ leak is substantial due to the large flux (number of channels recruited), leading to increased local Ca²⁺ concentrations, CaMKII activation, and further RyR sensitization, amplifying the leak. Conversely, in small clusters, the leak is limited, and sensitization is restricted. Furthermore, CaMKII activation can enhance late sodium (Na⁺) current, increasing Na⁺ influx and subsequently raising Ca²⁺ levels via the Na⁺-Ca²⁺ exchanger, further promoting Ca²⁺ leak and functional heterogeneity. We conclude that such positive feedback processes play a crucial role in arrhythmogenic Ca²⁺ wave initiation and propagation, particularly in heart failure myocytes where PTMs are often dysregulated.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073630","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":"Physical effects of crowdant size and concentration on collective microtubule polymerization.","authors":"Jashaswi Basu, Aman Soni, Chaitanya A Athale","doi":"10.1016/j.bpj.2025.01.020","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.01.020","url":null,"abstract":"<p><p>The polymerization of cytoskeletal filaments is regulated by both biochemical pathways, as well as physical factors such as crowding. The effect of crowding in vivo emerges from the density of intracellular components. Due to the complexity of the intracellular environment, most studies are based on either in vitro reconstitution or theory. Crowding agent (crowdants) size has been shown to influence polymerization of both actin and microtubules (MTs). Previously, the elongation rates of MT dynamics observed at single filament scale were reported to decrease with increasing concentrations of small but not large crowdants, and this correlated with in vivo viscosity increases. However, the exact nature of the connection between viscosity, crowdant size, nucleation and MT elongation has remained unclear. Here, we use in vitro reconstitution of bulk MT polymerization kinetics and microscopy to examine the collective effect of crowdant molecular weight, volume occupancy and viscosity on elongation and spontaneous polymerization. We find MT elongation rates obtained from bulk polymerization decrease in presence of multiple low molecular weight (LMW) crowdants, while increasing with high molecular weight (HMW) crowdants. Lattice Monte Carlo simulations of an effective model of collective polymerization demonstrate reduced polymerization rates arise due to decrease in monomer diffusion due to small sized crowdants. However, MT polymerization in the absence of nucleators, de novo, shows a crowdant size-independence of polymerization rate and critical concentration, depending solely on concentration of the crowdant. In microscopy, we find LMW crowdants result in short but many filaments, while HMW crowdants increase filament density, but have little effect on lengths. The effect of crowdant volume fraction ϕ_c and size in de novo polymerization match simulations, demonstrating crowdants affect elongation independent of nucleation. Thus, the effect of viscosity on collective MT dynamics, i.e. filament numbers and lengths, shows crowdant size dependence for elongation, but independence for de novo polymerization.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063188","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":"Transformer Graph Variational Autoencoder for Generative Molecular Design.","authors":"Trieu Nguyen, Aleksandra Karolak","doi":"10.1016/j.bpj.2025.01.022","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.01.022","url":null,"abstract":"<p><p>In the field of drug discovery, the generation of new molecules with desirable properties remains a critical challenge. Traditional methods often rely on SMILES (Simplified Molecular Input Line Entry System) representations for molecular input data, which can limit the diversity and novelty of generated molecules. To address this, we present the Transformer Graph Variational Autoencoder (TGVAE), an innovative AI model that employs molecular graphs as input data, thus captures the complex structural relationships within molecules more effectively than string models. To enhance molecular generation capabilities, TGVAE combines a Transformer, Graph Neural Network (GNN), and Variational Autoencoder (VAE). Additionally, we address common issues like over-smoothing in training GNNs and posterior collapse in VAE to ensure robust training and improve the generation of chemically valid and diverse molecular structures. Our results demonstrate that TGVAE outperforms existing approaches, generating a larger collection of diverse molecules and discovering structures that were previously unexplored. This advancement not only brings more possibilities for drug discovery but also sets a new level for the use of AI in molecular generation.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063210","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":"Synaptic cleft geometry modulates NMDAR opening probability by tuning neurotransmitter residence time.","authors":"María Hernández Mesa, Kimberly McCabe, Padmini Rangamani","doi":"10.1016/j.bpj.2025.01.019","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.01.019","url":null,"abstract":"<p><p>Synaptic morphology plays a critical role in modulating the dynamics of neurotransmitter diffusion and receptor activation in interneuron communication. Central physical aspects of synaptic geometry, such as the curvature of the synaptic cleft, the distance between the presynaptic and postsynaptic membranes, and the surface area-to-volume ratio of the cleft, crucially influence glutamate diffusion and N-Methyl-D-Aspartate receptor (NMDAR) opening probabilities. In this study, we developed a stochastic model for receptor activation using realistic synaptic geometries. Our simulations revealed substantial variability in NMDAR activation, showing the significant impact of synaptic structure on receptor activation. Next, we designed a theoretical study with idealized cleft geometries to understand the impact of different biophysical properties on receptor activation. Specifically, we found that increasing the curvature of the synaptic membranes could compensate for reduced NMDAR activation when the synaptic cleft width was large. Additionally, non-parallel membrane configurations, such as convex presynapses or concave postsynaptic densities (PSDs), maximize NMDAR activation by increasing the surface area-to-volume ratio, thereby increasing glutamate residence time and reducing glutamate escape. Furthermore, clustering NMDARs within the PSD significantly increased receptor activation across different geometric conditions and mitigated the effects of synaptic morphology on NMDAR opening probabilities. These findings highlight the complex interplay between synaptic geometry and receptor dynamics and provide important insights into how structural modifications can influence synaptic efficacy and plasticity. By considering the major physical factors that affect neurotransmitter diffusion and receptor activation, our work offers a comprehensive understanding of how variations in synaptic geometry regulate neurotransmission.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057950","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":"Competing addition processes give distinct growth regimes in the assembly of 1D filaments.","authors":"Sk Ashif Akram, Tyler Brown, Stephen Whitelam, Georg Meisl, Tuomas P J Knowles, Jeremy D Schmit","doi":"10.1016/j.bpj.2025.01.018","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.01.018","url":null,"abstract":"<p><p>We present a model to describe the concentration-dependent growth of protein filaments. Our model contains two states, a low entropy/high affinity ordered state and a high entropy/low affinity disordered state. Consistent with experiments, our model shows a diffusion-limited linear growth regime at low concentration, followed by a concentration-independent plateau at intermediate concentrations, and rapid disordered precipitation at the highest concentrations. We show that growth in the linear and plateau regions is the result of two processes that compete amid the rapid binding and unbinding of non-specific states. The first process is the addition of ordered molecules during periods in which the end of the filament is free of incorrectly bound molecules. The second process is the capture of defects, which occurs when consecutive ordered additions occur on top of incorrectly bound molecules. We show that a key molecular property is the probability that a diffusive collision results in a correctly bound state. Small values of this probability suppress the defect capture growth mode, resulting in a plateau in the growth rate when incorrectly bound molecules become common enough to poison ordered growth. We show that conditions that non-specifically suppress or enhance intermolecular interactions, such as the addition of depletants or osmolytes, have opposite effects on the growth rate in the linear and plateau regimes. In the linear regime, stronger interactions promote growth by reducing dissolution events, but in the plateau regime stronger interactions inhibit growth by stabilizing incorrectly bound molecules.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057948","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":"Channel rectification made simple.","authors":"Harley T Kurata, Christopher N Rowley","doi":"10.1016/j.bpj.2025.01.013","DOIUrl":"10.1016/j.bpj.2025.01.013","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036287","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}