Shalini J. Rukmani, Yan Yu, Mood Mohan, Vaidyanathan Sethuraman, Monojoy Goswami, Jeremy C. Smith
{"title":"Coarse-Grained Molecular Dynamics Simulation of Solvent-Dependent Cellulose Nanofiber Interactions","authors":"Shalini J. Rukmani, Yan Yu, Mood Mohan, Vaidyanathan Sethuraman, Monojoy Goswami, Jeremy C. Smith","doi":"10.1016/j.bpj.2025.08.021","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.08.021","url":null,"abstract":"Associations between cellulose are important both in biofuel production and in the use of cellulose for biomaterials. Cellulose nanofibers (CNFs) are sustainable, strong, light-weight alternatives to traditional materials in manufacturing, but are challenging to obtain due to irreversible aggregation in solution during preparative fibrillation. Therefore, it is imperative to understand the underlying factors driving aggregation with a view to designing solvents that can effectively compete with inter-fiber interactions, hence reducing aggregation. Molecular dynamics (MD) simulation at atomic detail can provide useful information on local interactions. However, the length and timescales accessible are too short to fully capture association processes. Here, we provide a method for accessing the longer length and timescales required using coarse-grained (CG) MD simulations with a MARTINI force field to calculate the interaction behavior of CNFs in three selected solvents: NaOH-urea-water, acetone, and neat water. The CG results are consistent with our prior all-atom MD and with previous experimental results. While acetone is found not to be an effective solvent, urea and ionic moieties in NaOH-urea-water not only solvate the fibrils but also improve the confinement of water molecules around them as shown by the solvent residence times and mean-square displacements. Overall, the presence of urea and ions reduces the likelihood of aggregation in multi-CNF systems relative to neat water irrespective of whether the hydrophobic or hydrophilic CNF surfaces are interacting. The CG method shows clear promise for selecting potential high-performance solvents for experimental prioritization in bioenergy and biomaterials research in a relatively fast manner as well as for understanding the aggregation and rheological behavior of CNF-solvent systems.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144920665","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":"Dynamical properties of chromatin provide insights into key folding principles","authors":"Sangram Kadam, Soudamini Sahoo, P.B.Sunil Kumar, Ranjith Padinhateeri","doi":"10.1016/j.bpj.2025.08.018","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.08.018","url":null,"abstract":"Even though the three-dimensional static organization of chromatin is highly studied, chromatin is a dynamic structure, and time-dependent changes are crucial for biological function. While it is known that both intra-chromatin interaction and loop extrusion are crucial to understanding chromatin organization, what their respective roles are in deciding the nature of spatial and temporal organization is not clear. Simulating a model with active loop extrusion and intra-chromatin interactions, we show that under certain conditions, the measurable dynamic quantities are dominated by the loop extrusion, even though the population-averaged contact map (structure) can be dominated by intra-chromatin interactions, with loop extrusion playing no major role. Our results show that the dynamic scaling exponents with loop extrusion are consistent with the experimental observations and can be very different from those predicted by existing fractal-globule models for chromatin. We argue that one needs to measure both the structure and dynamics simultaneously to unambiguously interpret the organization of chromatin.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"27 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900460","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}
Timothy S. Carpenter, Fikret Aydin, Chris Neale, Que N. Van, Xiaohua Zhang, Harsh Bhatia, Jason W. Sidabras, Peter H. Frank, Konstantia Georgouli, Jeremy O.B. Tempkin, Violeta Burns Casamayor, Gulcin Gulten, Rebika Shrestha, Debanjan Goswami, Francesco Di Natale, Joseph R. Chavez, Adam Moody, Joseph Y. Moon, Tomas Oppelstrup, James N. Glosli, Gautham Dharuman, Sergio Wong, Shusen Liu, Nicolas W. Hengartner, Cesar A. López, Kien Nguyen, Christopher B. Stanley, Liam G. Stanton, Lara Patel, Tyler Reddy, Thomas J. Turbyville, Brian Van Essen, Peer-Timo Bremer, Felice C. Lightstone, Andrew G. Stephen, Sandrasegaram Gnanakaran, Frank McCormick, Dwight V. Nissley, Frederick H. Streitz, Helgi I. Ingólfsson
{"title":"Dynamics and lipid membrane coupling of the RAS-RAF complex revealed via multiscale simulations","authors":"Timothy S. Carpenter, Fikret Aydin, Chris Neale, Que N. Van, Xiaohua Zhang, Harsh Bhatia, Jason W. Sidabras, Peter H. Frank, Konstantia Georgouli, Jeremy O.B. Tempkin, Violeta Burns Casamayor, Gulcin Gulten, Rebika Shrestha, Debanjan Goswami, Francesco Di Natale, Joseph R. Chavez, Adam Moody, Joseph Y. Moon, Tomas Oppelstrup, James N. Glosli, Gautham Dharuman, Sergio Wong, Shusen Liu, Nicolas W. Hengartner, Cesar A. López, Kien Nguyen, Christopher B. Stanley, Liam G. Stanton, Lara Patel, Tyler Reddy, Thomas J. Turbyville, Brian Van Essen, Peer-Timo Bremer, Felice C. Lightstone, Andrew G. Stephen, Sandrasegaram Gnanakaran, Frank McCormick, Dwight V. Nissley, Frederick H. Streitz, Helgi I. Ingólfsson","doi":"10.1016/j.bpj.2025.08.020","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.08.020","url":null,"abstract":"To gain molecular and mechanistic insights into initiation of the RAS-RAF signaling cascade we developed and used a combination of multiscale simulation and experimental approaches. The influence and impact of the membrane on RAS and RAF proteins is a factor we are just beginning to understand and appreciate in more detail. Molecular simulation is an ideal methodology to further study this complicated relationship between the membrane and associated proteins. Our previous work using MuMMI (Multiscale Machine-learned Modeling Infrastructure) investigated different lipid compositions solely around the KRAS4b protein and the interplay between protein behavior and these membrane environments. MuMMI uses machine learning to couple adjacent simulation scales and has been efficiently scaled across some of the world’s largest high-performance computers. Recently, we have expanded this multi-resolution framework to include the all-atom simulation scale, and to incorporate the RAF RBDCRD domains. Here we present the overall analysis results from this new simulation campaign comprising a mixture of RAS and RAF RBDCRD proteins. Approximately 35,000 coarse-grained, and 10,000 all-atom molecular dynamics simulations were completed, sampled from a variety of protein/lipid composition configurations that were generated from a micron-scale continuum simulation containing hundreds of copies of the proteins.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"3 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900457","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":"Membrane remodeling by the caveolin-1 8s oligomeric complex","authors":"Hrushikesh Malshikare, Durba Sengupta","doi":"10.1016/j.bpj.2025.08.019","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.08.019","url":null,"abstract":"Caveolin-1 is a scaffolding protein crucial for the formation of caveolae, specialized membrane structures that are involved in diverse cellular processes such as endocytosis, mechano-sensing, and lipid regulation. Recently, a unique structure of the 8S oligomeric complex of caveolin-1 was resolved by cryo-electron microscopy, providing a foundational basis for understanding its molecular mechanisms. In this study, we probe the membrane interactions of the oligomeric caveolin-1 complex in membrane lipid bilayers and vesicles. We performed coarse-grain molecular dynamics simulations to delineate the interactions of the palmitoylated and non-palmitoylated caveolin-1 with multi-component membranes. During the simulations, the caveolin-1 complex binds to the membranes, partially to one of the leaflets in a shallow monotopic arrangement. A remodeling of the lipids in its vicinity of the complex was observed in both vesicles and planar bilayers. However, the caveolin-1 complex binds to vesicles without inducing any significant change to the curvature, whereas it appears to induce increased curvature in the planar bilayers leading to the formation of highly curved nanodomains. Cholesterol and phosphoserine lipid enrichment, hallmarks of caveolin-1 binding, were observed in a membrane-topology dependent manner. The differential cholesterol clustering observed between vesicles and bilayers, highlights the curvature-dependent nature of caveolin-1-mediated lipid organization. Our work highlights the dual significance of lipid organization and membrane topology in the functional dynamics of caveolin-1, shedding light on its role in inducing and sensing membrane curvature, which is pivotal for various cellular processes.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"22 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900459","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":"Branching, crosslinking and decentralization of microtubules accelerates intracellular assembly","authors":"Apurba Sarkar, Alex Mogilner, Raja Paul","doi":"10.1016/j.bpj.2025.08.016","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.08.016","url":null,"abstract":"Before cell division, mitotic spindle is assembled from chromosomes and centrosomes. After the cell division, Golgi organelles assemble from multiple vesicles scattered across daughter cells. These are among many other examples of intracellular assembly of vesicles, organelles and chromosomes made possible by dynamic microtubules. The most prominent microtubule networks are centrosome-focused asters that ‘search’ for the vesicles and chromosomes, but there are also microtubules originating from the vesicles and chromosomes, raising the question whether a coordination between multiple microtubule networks optimizes the assembly process. This study uses a computational model to examine how microtubule dynamics influence the assembly of organelles from vesicles. The model includes two microtubule populations: microtubules anchored to the vesicles, which drive local clustering, and ‘central’ microtubules anchored to the centrosome that aggregate the vesicles globally. Simulations show that a microtubule decentralization – balanced contribution from both microtubule populations — accelerates the assembly of tens of vesicles, but that assigning all microtubules to hundreds of vesicles optimizes the assembly. Directionally biased microtubule growth, particularly when avoiding spontaneous catastrophe events, further accelerates the assembly. Additionally, microtubule branching, when occurring at optimal angles and spacings, enhances the assembly’s efficiency. Lastly, rapid crosslinking of overlapping central and ‘local’ microtubules can drastically accelerate the assembly. Applying this model to the spindle assembly in early mitosis reveals similar insights. The model suggests that the observed multiple microtubule networks optimize the intracellular assembly processes when molecular resources are limited.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"7 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900462","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}
Chiara Mattamira, Alyssa Ward, Sriram Tiruvadi Krishnan, Rajan Lamichhane, Francisco N. Barrera, Ioannis Sgouralis
{"title":"Bayesian analysis and efficient algorithms for single-molecule fluorescence data and step counting","authors":"Chiara Mattamira, Alyssa Ward, Sriram Tiruvadi Krishnan, Rajan Lamichhane, Francisco N. Barrera, Ioannis Sgouralis","doi":"10.1016/j.bpj.2025.08.014","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.08.014","url":null,"abstract":"With the growing adoption of single-molecule fluorescence experiments, there is an increasing demand for efficient statistical methodologies and accurate analysis of the acquired measurements. Existing analysis frameworks, such as those that use kinetic models, often rely on strong assumptions on the dynamics of the molecules and fluorophores under study that render them inappropriate for general purpose step counting applications, especially when the systems of study exhibit uncharacterized dynamics. Here, we propose a novel Bayesian nonparametric framework to analyze single-molecule fluorescence data that is kinetic model independent. For the evaluation of our methods, we develop four MCMC samplers, ranging from elemental to highly sophisticated, and demonstrate that the added complexity is essential for accurate data analysis. We apply our methods to experimental data obtained from TIRF photobleaching assays of the EphA2 receptor tagged with GFP. In addition, we validate our approach with synthetic data mimicking realistic conditions and demonstrate its ability to recover ground truth under high- and low-signal-to-noise data, establishing it as a versatile tool for fluorescence data analysis.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"7 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900464","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}
Biophysical journalPub Date : 2025-08-19Epub Date: 2025-07-05DOI: 10.1016/j.bpj.2025.06.040
Van N T La, Lulu Kang, David D L Minh
{"title":"Enzyme kinetics model for the coronavirus main protease including dimerization and ligand binding.","authors":"Van N T La, Lulu Kang, David D L Minh","doi":"10.1016/j.bpj.2025.06.040","DOIUrl":"10.1016/j.bpj.2025.06.040","url":null,"abstract":"<p><p>The coronavirus main protease (MPro) plays a pivotal role in viral replication and is the target of multiple antiviral drug discovery campaigns against SARS-CoV-2. In some species, CRCs of MPro enzymatic activity can exhibit biphasic behavior in which low ligand concentrations activate the enzyme, whereas higher ones inhibit it. While this behavior has been attributed to ligand-induced dimerization, quantitative enzyme kinetics models have not been fit to it. Here, we develop a kinetic model integrating dimerization and ligand binding. We perform a Bayesian regression to globally fit the model to multiple types of biochemical and biophysical data. The reversible covalent inhibitor GC376 strongly induces dimerization and binds to the dimer with positive cooperativity. In contrast, the fluorescent peptide substrate has a minor effect on dimerization but binds to the dimer with negative cooperativity. The biphasic concentration response curve occurs because, compared with substrate, the inhibitor accelerates turnover in the opposite catalytic site.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"2627-2638"},"PeriodicalIF":3.1,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567029","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}
Biophysical journalPub Date : 2025-08-19Epub Date: 2025-07-02DOI: 10.1016/j.bpj.2025.06.041
Koen R Storm, Caroline Körösy, Enrico Skoruppa, Stefanie D Pritzl, Pauline J Kolbeck, Willem Vanderlinden, Helmut Schiessel, Jan Lipfert
{"title":"The effects of DMSO on DNA conformations and mechanics.","authors":"Koen R Storm, Caroline Körösy, Enrico Skoruppa, Stefanie D Pritzl, Pauline J Kolbeck, Willem Vanderlinden, Helmut Schiessel, Jan Lipfert","doi":"10.1016/j.bpj.2025.06.041","DOIUrl":"10.1016/j.bpj.2025.06.041","url":null,"abstract":"<p><p>Dimethyl sulfoxide (DMSO) is a polar aprotic solvent used in a wide range of applications, including uses as a drug and in drug delivery, as a solvent for fluorescent dyes, and in enzymatic reactions that process DNA. Consequently, many assays contain low concentrations (≤10%) of DMSO. While it is well known that DMSO lowers the melting temperature of DNA, its effects on DNA conformations and mechanical properties below the melting temperature are unclear. Here, we use complementary single-molecule techniques to probe DNA in the presence of 0-60% DMSO. Magnetic tweezers force-extension measurements find that the bending persistence length of DNA decreases moderately and linearly with DMSO concentrations up to 20 vol %, by (0.43 ± 0.02%) per %-DMSO. Magnetic tweezers twist measurements demonstrate a reduction in melting torque in the presence of DMSO and find that the helical twist of DNA remains largely unchanged up to 20% DMSO, while even higher concentrations slightly unwind the helix. Using AFM imaging, we find a moderate compaction of DNA conformations by DMSO and observe a systematic decrease of the mean-squared end-to-end distance by 1.2% per %-DMSO. We use coarse-grained Monte Carlo simulations of DNA as a semiflexible polymer with a variable density of flexible segments, representing DMSO-induced local defects or melting, to rationalize the observed behavior. The model quantitates the effects of introducing locally flexible regions into DNA and gives trends in line with the magnetic tweezers and AFM imaging experiments. Our results show that addition of up to 50% DMSO has a gradual effect on DNA structure and mechanics and that, for low concentrations (≤20%), the induced changes are relatively minor. Our work provides a baseline to understand and model the effects of DMSO on DNA in a range of biophysical and biochemical assays.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"2639-2654"},"PeriodicalIF":3.1,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551851","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}
Biophysical journalPub Date : 2025-08-19Epub Date: 2025-07-12DOI: 10.1016/j.bpj.2025.07.009
Anthony J Baker, On Yeung Li, Filip Ježek, Paul C Simpson, Naomi C Chesler, Daniel A Beard
{"title":"Ca<sup>2+</sup> increases cardiac muscle viscoelasticity independent of active force development.","authors":"Anthony J Baker, On Yeung Li, Filip Ježek, Paul C Simpson, Naomi C Chesler, Daniel A Beard","doi":"10.1016/j.bpj.2025.07.009","DOIUrl":"10.1016/j.bpj.2025.07.009","url":null,"abstract":"<p><p>In addition to activation of muscle contraction by Ca<sup>2+</sup>, previous studies suggest that Ca<sup>2+</sup> also affects muscle passive mechanical properties. The goal of this study was to determine if Ca<sup>2+</sup> regulates the stiffness of cardiac muscle, independent of active contraction. The mechanical response to stretch for mouse demembranated cardiac trabeculae was probed at different Ca<sup>2+</sup> levels after eliminating active contraction using a combination of two myosin ATPase inhibitors: para-nitroblebbistatin (PNB; 50 μM) plus mavacamten (Mava; 50 μM). Myocardial force level was assessed during large stretches (≈20% initial muscle length) with a range of stretch velocities. For relaxed muscle, in response to stretch, muscle force rose to a peak and then decayed toward a lower steady-state level. Peak force was higher with faster stretch velocity, consistent with the presence of a viscoelastic element. However, the steady-state force was independent of stretch velocity, consistent with the presence of an elastic component. In the presence of the inhibitors PNB plus Mava, when the Ca<sup>2+</sup> level was increased, active contraction was completely prevented. However, the viscoelastic force response to stretch was markedly increased by high Ca<sup>2+</sup> and was >sixfold higher than at the low Ca<sup>2+</sup> level. The relationship of viscoelastic force to Ca<sup>2+</sup> level had a similar form to the relationship of active force to Ca<sup>2+</sup> (measured in the absence of inhibitors), suggesting that a common regulatory mechanism is involved. As expected, Ca<sup>2+</sup>-activated contraction was inhibited by lowering the temperature from 21°C to 10°C. In contrast, the Ca<sup>2+</sup>-activated viscoelastic property was not inhibited at lower temperatures, further suggesting that active contraction and the viscoelastic property involve distinct mechanisms. This study demonstrates that in addition to triggering activation of contraction, Ca<sup>2+</sup> also increases the apparent viscoelastic property of cardiac muscle.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"2698-2707"},"PeriodicalIF":3.1,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616119","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}
Biophysical journalPub Date : 2025-08-19Epub Date: 2025-07-21DOI: 10.1016/j.bpj.2025.07.017
Daisuke Sato, Bence Hegyi, Crystal M Ripplinger, Donald M Bers
{"title":"Role of dynamical instability in QT interval variability and early afterdepolarization propensity.","authors":"Daisuke Sato, Bence Hegyi, Crystal M Ripplinger, Donald M Bers","doi":"10.1016/j.bpj.2025.07.017","DOIUrl":"10.1016/j.bpj.2025.07.017","url":null,"abstract":"<p><p>Beat-to-beat variability of the QT interval (QTV) is a well-established marker of cardiac health, with increased QTV (>5 ms) often associated with a higher risk of arrhythmias. However, the underlying mechanisms contributing to this phenomenon remain poorly understood. Recently, we showed that cardiac instability is a major cause of QTV. Early afterdepolarizations (EADs) are abnormal electrical oscillations that occur during the plateau phase of the cardiac action potential (AP), often arising when the membrane potential becomes unstable. In this study, we use a physiologically detailed computational model of rabbit ventricular myocytes with stochastic ion channel gating to investigate the relationship between QTV and EAD propensity. We found that increased AP duration (APD) variability, which serves as a surrogate for QTV on the electrocardiogram at the single-cell level, can arise even in the absence of apparent EADs, driven by intrinsic dynamical instability. As the cellular state approaches the threshold for EAD generation, small perturbations in membrane voltage are amplified, leading to increased APD variability. The phase-plane analysis in the voltage-calcium channel inactivation space demonstrates that proximity to the EAD-generating basin of attraction strongly influences repolarization variability, establishing a mechanistic link between QTV and EAD propensity. Furthermore, we observed that QTV increases at longer pacing cycle lengths (PCLs), distinguishing it from alternans-associated APD variability, which increases at shorter PCLs. These findings suggest that increased QTV may serve as an early indicator of arrhythmic risk before the manifestation of EADs, potentially offering a critical window for preventive intervention. Our results provide novel insights into the fundamental mechanisms underlying QTV and its potential role in arrhythmia prediction.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"2768-2777"},"PeriodicalIF":3.1,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688790","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}