Biophysical journal最新文献

{"title":"Dynamical instability is a major cause of cardiac action potential variability.","authors":"Daisuke Sato, Bence Hegyi, Crystal M Ripplinger, Donald M Bers","doi":"10.1016/j.bpj.2025.02.007","DOIUrl":"10.1016/j.bpj.2025.02.007","url":null,"abstract":"<p><p>Increased beat-to-beat QT interval variability (QTV) in the electrocardiogram is strongly associated with ventricular arrhythmias and sudden cardiac death, yet its origins remain poorly understood. While heart rate variability decreases with deteriorating cardiac health, QTV increases, suggesting distinct underlying mechanisms. The stochastic nature of ion channel gating is a potential source of cardiac variability. However, the law of large numbers suggests that, with billions of channels in the heart, this stochasticity should be minimized. In this study, we tested the hypothesis that dynamical instability amplifies stochastic ion channel fluctuations, leading to increased action potential (AP) variability. Using a mathematical model of ventricular myocytes, we investigated the relationship between AP variability and voltage instability. Our results demonstrate that stochastic gating alone cannot cause large AP variability, but dynamical instability significantly amplifies this variability. We found a positive correlation between voltage instability, indicated by the slope of the AP duration restitution curve, and AP duration variability. Notably, the largest variability occurred at the onset of alternans when considering every other beat. These findings provide a mechanistic explanation for increased QTV in pathological conditions and suggest that measuring QTV using every other beat may predict the onset of alternans and severity of alternans. Our study highlights the critical role of dynamical instability in cardiac electrical variability and offers new insights into the mechanisms underlying arrhythmogenesis.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1042-1048"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405271","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":"Sphingomyelin slows interfacial hydrogen-bonding dynamics in lipid membranes.","authors":"Cong Xu, James E Fitzgerald, Edward Lyman, Carlos R Baiz","doi":"10.1016/j.bpj.2025.02.020","DOIUrl":"10.1016/j.bpj.2025.02.020","url":null,"abstract":"<p><p>Interfacial hydrogen bonding (H-bonding) partly determines membrane structure, heterogeneity, and dynamics. Given the chemical diversity of lipids, it is important to understand how composition determines lipid-lipid interactions and how those are translated to H-bond populations and dynamics. Here, we investigate the role of palmitoyl sphingosylphosphorylcholine (PSM) in modulating lipid H-bond networks in combination with dipalmitoyl phosphatidylcholine (DPPC) using ultrafast two-dimensional infrared (2D IR) spectroscopy and molecular dynamics simulations. We report composition-dependent H-bond ensembles for ester and amide carbonyls, with increased H-bond populations and slower dynamics with higher PSM concentrations. Specifically, amide carbonyl 2D IR spectra indicate that PSM, acting as an H-bond donor, partially replaces water-mediated interactions, with the number of direct lipid-lipid H-bonds constituting up to 20% of the total. These interactions create comparatively stable H-bond networks that significantly slow interfacial dynamics. 2D IR spectra show an H-bond lifetime slowdown of 45% in an equimolar mixture of the two lipids compared to DPPC alone. This study highlights PSM's dual role in H-bonding, which increases membrane viscosity and stabilizes lipid interfaces, providing molecular insights into the role of sphingolipids in cell membranes. The findings further emphasize the synergy of experimental and computational approaches for extracting molecular-level insights into interfacial lipid-lipid and lipid-water interactions in heterogeneous membranes.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1158-1165"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522530","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":"Quality control maps: Real-time quantitative control of single-molecule localization microscopy data.","authors":"Sébastien Mailfert, Meriem Djendli, Roxane Fabre, Didier Marguet, Nicolas Bertaux","doi":"10.1016/j.bpj.2025.02.018","DOIUrl":"10.1016/j.bpj.2025.02.018","url":null,"abstract":"<p><p>Single-molecule localization microscopy (SMLM) has revolutionized the understanding of cellular organization by reconstructing informative images with quantifiable spatial distributions of molecules far beyond the optical diffraction limit. Much effort has been devoted to optimizing localization accuracy. One such approach is the assessment of SMLM data quality in real time rather than after lengthy postacquisition analysis, which nevertheless represents a computational challenge We overcame this difficulty by implementing an innovative mathematical approach we designed to drastically reduce the computational analysis of particle localization. Our quality control maps (QCM) workflow enables a much higher rate of data processing compared to that limited by the frequency required by current cameras. Accordingly, using an innovative computational approach for the detection step and an estimator based on a Gaussian model of the point spread function, subpixel particle locations and their accuracy can be determined through a straightforward analytical calculation without the need for iterations. As a true parameter-free algorithm, QCM is robust and adaptable to all types of SMLM data, with high speed enabling the real-time calculation of quantitative quality control indicators. Such features are compatible with smart microscopy, the concept of which depends on the adjustment of acquisition parameters in real time according to analytical results. Finally, the offline QCM mode can be used as a tool to evaluate synthetic or previously acquired data, as well as to teach the basic concepts of SMLM.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1132-1145"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514659","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":"Morphological trapping of neurotransmitters in synaptic clefts: A new dimension in neural plasticity.","authors":"Bugra Kaytanli, Mattia Bacca","doi":"10.1016/j.bpj.2025.02.026","DOIUrl":"10.1016/j.bpj.2025.02.026","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1035-1037"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536384","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":"Flipping the switch: Illuminating inverted ligand activation of peptide-gated ion channels.","authors":"Wassim Elkhatib, Adriano Senatore","doi":"10.1016/j.bpj.2025.02.027","DOIUrl":"10.1016/j.bpj.2025.02.027","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1038-1041"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555798","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 J McCabe, Padmini Rangamani","doi":"10.1016/j.bpj.2025.01.019","DOIUrl":"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 a 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, nonparallel membrane configurations, such as convex presynapses or concave postsynaptic densities, 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 postsynaptic density 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 may regulate neurotransmission.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1058-1072"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","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":"Further exploration of the quantitative distance-energy and contact number-energy relationships for predicting the binding affinity of protein-ligand complexes.","authors":"Yong Xiao Yang, Bao Ting Zhu","doi":"10.1016/j.bpj.2025.02.021","DOIUrl":"10.1016/j.bpj.2025.02.021","url":null,"abstract":"<p><p>Accurate estimation of the strength of the protein-ligand interaction is important in the field of drug discovery. The binding strength can be determined by using experimental binding affinity assays which are both time and labor consuming and costly. Predicting the binding affinity/energy in silico is an alternative approach, particularly for virtual screening of large data sets. In general, the distance-based terms such as electrostatic and van der Waals interactions are among the key determinants of binding energy. In this work, the distance-binding energy relationships, i.e., E ∝ -d^-k, are further explored, extended, and developed for protein-ligand binding affinity prediction. The contributions of different atom-type pairs were considered synthetically and jointly. Additionally, the contact number-energy relationships (E ∝ -n^k) were also explored for protein-ligand binding affinity prediction. Significantly, the power exponents of the distances or contact numbers in the energy functions are not restricted by the existing theories concerning van der Waals and electrostatic energies (expressed as ar⁶-br¹² and cr). The performances of the new distance-based or contact number-based models are better than the performances of those sophisticated non-machine-learning-based scoring functions developed before. The exploration and extension of the distance-energy and contact number-energy relationships may offer insights into the development of more effective methods for predicting the protein-ligand binding affinity accurately and analyzing the protein-ligand interactions rationally.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1166-1177"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522527","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":"Flipped binding modes for the same agonist in closely related neuropeptide-gated ion channels.","authors":"Emily J S Claereboudt, Mowgli Dandamudi, Léa Longueville, Hassan Y Harb, Timothy Lynagh","doi":"10.1016/j.bpj.2025.01.004","DOIUrl":"10.1016/j.bpj.2025.01.004","url":null,"abstract":"<p><p>Neuropeptides are inter-cellular signaling molecules occurring throughout animals. Most neuropeptides bind and activate G-protein-coupled receptors, but some also activate ionotropic receptors (or \"ligand-gated ion channels\"). This is exemplified by the tetra-peptide H-Phe-Met-Arg-Phe-NH₂ (FMRFamide (FMRFa)), which activates mollusk and annelid FMRFa-gated sodium channels (FaNaCs) from the trimeric degenerin/epithelial sodium channel superfamily. Here, we explored the structure-activity relationships determining FMRFa potency at mollusk and annelid FaNaCs in the light of emerging structural data, using synthetic neuropeptide analogs, heterologous expression, and two-electrode voltage clamp. Substitutions of the FMRFa N-terminal phenylalanine residue (F1) and methionine residue (M2) decreased or abolished FMRFa potency at mollusk Aplysia kurodai FaNaC but had little effect at annelid Malacoceros fuliginosus FaNaC1. Conversely, F4 substitutions had little effect on FMRFa potency at A. kurodai FaNaC but either abolished, strongly decreased, or slightly increased potency at M. fuliginosus FaNaC1. Accordingly, recently published high-resolution FaNaC structures show that F1 and F4 residues orient deep into the neuropeptide-binding pockets of A. kurodai FaNaC and M. fuliginosus FaNaC1, respectively. We also use noncanonical amino acid substitutions in A. kurodai FaNaC to describe the physico-chemical determinants of FMRFa F1 binding to A. kurodai FaNaC aromatic side chains. Our results show that the \"deeper\" of the two FMRFa phenylalanine residues in the binding pocket is crucial for FMRFa potency despite the peptide orienting very differently into the homologous binding sites of two closely related receptors.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1049-1057"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969460","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":"Conformational equilibrium of an ABC transporter analyzed by luminescence resonance energy transfer.","authors":"Maria E Zoghbi, Annabella Nouel Barreto, Alex L Hernandez","doi":"10.1016/j.bpj.2025.02.016","DOIUrl":"10.1016/j.bpj.2025.02.016","url":null,"abstract":"<p><p>Humans have three known ATP-binding cassette (ABC) transporters in the inner mitochondrial membrane (ABCB7, ABCB8, and ABCB10). ABCB10, the most studied of them thus far, is essential for normal red blood cell development and protection against oxidative stress, and it was recently found to export biliverdin, a heme degradation product with antioxidant properties. The molecular mechanism underlying the function of ABC transporters remains controversial. Their nucleotide binding domains (NBDs) must dimerize to hydrolyze ATP, but capturing the transporters in such conformation for structural studies has been experimentally difficult, especially for ABCB10 and related eukaryotic transporters. Purified transporters are commonly studied in detergent micelles, or after their reconstitution in nanodiscs, usually at nonphysiological temperature and using nonhydrolyzable ATP analogs or mutations that prevent ATP hydrolysis. Here, we have used luminescence resonance energy transfer to evaluate the effect of experimental conditions on the NBD dimerization of ABCB10. Our results indicate that all conditions used for determination of currently available ABCB10 structures have failed to induce NBD dimerization. ABCB10 in detergent responded only to MgATP at 37°C, whereas reconstituted protein shifted toward dimeric NBDs more easily, including in response to MgAMP-PNP and even present NBD dimerization with MgATP at room temperature. The nanodisc's size affects the nucleotide-free conformational equilibrium of ABCB10 and the response to ATP in the absence of magnesium, but for all analyzed sizes (scaffold proteins MSP1D1, MSP1E3D1, and MSP2N2), a conformation with dimeric NBDs is clearly preferred during active ATP hydrolysis (MgATP, 37°C). These results highlight the sensitivity of this human ABC transporter to experimental conditions and the need for a more cautious interpretation of structural models obtained under far from physiological conditions. A dimeric NBD conformation that has been elusive in previous studies seems to be dominant during MgATP hydrolysis at physiological temperature.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"1117-1131"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456401","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":"Mechanical adaptivity of red blood cell flickering to extrinsic membrane stiffening by the solid-like biosurfactant β-Aescin.","authors":"Lara H Moleiro, Diego Herráez-Aguilar, Guillermo Solís-Fernández, Niccolo Caselli, Carina Dargel, Verónica I Dodero, José M Bautista, Thomas Hellweg, Francisco Monroy","doi":"10.1016/j.bpj.2025.03.027","DOIUrl":"https://doi.org/10.1016/j.bpj.2025.03.027","url":null,"abstract":"<p><p>β-Aescin is a natural additive employed for treatments of vascular insufficiency, hence its impact in red blood cell (RBC)'s adaptivity has been conjectured. Here, we report a study about the mechanical impact of the membrane stiffener aescin on the flickering motions of live RBCs maintained at the homeostatic status. An active flickering, or nonequilibrium fluctuation dynamics has been revealed by mapping flickering motions in single RBCs treated or not with aescin. Experiments show that active RBC flickers adapt mechanically to β-escin, unlike the passive thermal fluctuations observed in lipid bilayers without an active skeleton. Mechanical connections for active flickering are theoretically argued to exist between an effective viscoelastic softness bestowed by the spectrin membrane cytoskeleton and the observed stiffness imposed by aescin as a rigidity modulator. From the unveiled diffusive mechanics, we model an adaptive RBC homeostasis that recapitulates the active flickering phenomenon as an optimal membrane softness upon a regulated friction as observed under aescin-induced membrane hardening. From a physiological perspective, RBC flicker adaptiveness to rigidization is discussed according to regulatory principles of energy conservation and minimal dissipation.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771221","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}