Biophysical journal最新文献

The process of biological fate decision regulated by gene regulatory networks involves numerous complex dynamical interactions among many components. Mathematical modeling typically employed ordinary differential equations and steady-state analysis, which has yielded valuable quantitative insights. However, stable states predicted by theoretical models often fail to capture transient or metastable phenomena that occur during most observation periods in experimental or real biological systems. We attribute this discrepancy to the omission of dynamic processes of various complex interactions. Here, we demonstrate the influence of delays in gene regulatory steps and the timescales of the external induction on the dynamic processes of the fate decision in inducible bistable systems. We propose that steady-state parameters determine the landscape of fate decision. However, during the dynamic evolution along the landscape, the unequal delays of biochemical interactions as well as the timescale of external induction cause deviations in the differentiation trajectories, leading to the formation of new transient distributions that persist long term. Our findings emphasize the importance of considering dynamic processes in fate decision instead of relying solely on steady-state analysis. We provide insights into the interpretation of experimental phenomena and offer valuable guidance for future efforts in dynamical modeling and synthetic biology design.

The dissipation of electrochemical gradients through ion channels plays a central role in biology. Herein we use voltage-responsive kinetic models of ion channels to explore how electrical and chemical potentials differentially influence ion transport properties. These models demonstrate how electrically driven flux is greater than the Nernstian equivalent chemically driven flux yet still perfectly cancels when the two gradients oppose each other. We find that the location and relative stability of ion-binding sites dictates rectification properties by shifting the location of the most voltage-sensitive transitions. However, these rectification properties invert when bulk concentrations increase relative to the binding-site stabilities, moving the rate-limiting steps from uptake into a relatively empty channel to release from an ion-blocked full channel. Additionally, the origin of channel saturation is shown to depend on the free energy of uptake relative to bulk concentrations. Collectively these insights provide a framework for interpreting and predicting how channel properties manifest in electrochemical transport behavior.

We elucidate the mechanism underpinning a recently discovered phenomenon in which cells respond to MHz-order mechanostimuli. Deformations induced along the plasma membrane under these external mechanical cues are observed to decrease the membrane tension, which, in turn, drives transient and reversible remodeling of its lipid structure. In particular, the increase and consequent coalescence of ordered lipid microdomains leads to closer proximity to mechanosensitive ion channels-Piezo1, in particular-that, due to crowding, results in their activation to mobilize influx of calcium (Ca²⁺) ions into the cell. It is the modulation of this second messenger that is responsible for the downstream signaling and cell fates that ensue. In addition, we show that such spatiotemporal control over the membrane microdomains in cells-without necessitating biochemical factors-facilitates aggregation and association of intrinsically disordered tau proteins in neuroblastoma cells, and their transformation to pathological conditions implicated in neurodegenerative diseases, thereby paving the way for the development of therapeutic intervention strategies.

The development of methods that allow a structural interpretation of linear and nonlinear vibrational spectra is of great importance, both for spectroscopy and for optimizing force field quality. The experimentally measured signals are ensemble averages over all accessible configurations, which complicates spectral calculations. To account for this, we present a recipe for calculating vibrational amide-I spectra of proteins based on metadynamics molecular dynamics simulations. For each frame, a one-exciton Hamiltonian is set up for the backbone amide groups, in which the couplings are estimated with the transition-charge coupling model for nonnearest neighbors, and with a parametrized map of ab initio calculations that give the coupling as a function of the dihedral angles for nearest neighbors. The local-mode frequency variations due to environmental factors such as hydrogen bonds are modeled by exploiting the linear relationship between the amide C-O bond length and the amide-I frequency. The spectra are subsequently calculated while taking into account the equilibrium statistical weights of the frames that are determined using a previously published reweighting procedure. By implementing all these steps in an efficient Fortran code, the spectra can be averaged over very large amounts of structures, thereby extensively covering the phase space of proteins. Using this recipe, the spectral responses of 2.5 million frames of a metadynamics simulation of the miniprotein Trp-cage are averaged to reproduce the experimental temperature-dependent IR spectra very well. The spectral calculations provide new insight into the origin of the various spectral signatures (which are typically challenging to disentangle in the congested amide-I region), and allow for a direct structural interpretation of the experimental spectra and for validation of the molecular dynamics simulations of ensembles.

Desensitization is a prominent feature of nearly all ligand-gated ion channels. Acid-sensing ion channels (ASICs) undergo desensitization within hundreds of milliseconds to seconds upon continual extracellular acidification. The ASIC mechanism of desensitization is primarily due to the isomerization or "flipping" of a short linker joining the 11th and 12th β sheets in the extracellular domain. In the resting and active states this β11-12 linker adopts an "upward" conformation while in the desensitized conformation the linker assumes a "downward" state. It is unclear if a single linker adopting the downward state is sufficient to desensitize the entire channel, or if all three are needed or some more complex scheme. To accommodate this downward state, specific peptide bonds within the linker adopt either trans-like or cis-like conformations. Since proline-containing peptide bonds undergo cis-trans isomerization very slowly, we hypothesized that introducing proline residues in the linker may slow or even abolish ASIC desensitization, potentially providing a valuable research tool. Proline substitutions in the chicken ASIC1 β11-12 linker (L414P and Y416P) slowed desensitization decays approximately 100- to 1000-fold as measured in excised patches. Both L414P and Y416P shifted the steady-state desensitization curves to more acidic pH values while activation curves and ion selectivity were largely unaffected (except for a left-shifted activation pH₅₀ of L414P). To investigate the functional stoichiometry of desensitization in the trimeric ASIC, we created families of L414P and Y416P concatemers with zero, one, two, or three proline substitutions in all possible configurations. Introducing one or two L414P or Y416P substitutions only slightly attenuated desensitization, suggesting that conformational changes in the single remaining faster wild-type subunits were sufficient to desensitize the channel. These data highlight the unusual cis-trans isomerization mechanism of ASIC desensitization and support a model where ASIC desensitization requires only a single subunit.

We propose a model for the feedback control processes that underlie the robustness and high sensitivity of mechanosensory hair cells. Our model encompasses self-tuning active processes intrinsic to these cells, which drive the amplification of mechanical stimuli by consuming metabolic energy, and a neural input process that protects these cells from damage caused by powerful stimuli. We explore the effects of these two feedback mechanisms on mechanical self-oscillations of the sense cells and their response to external forcing.

The C9orf72 gene associated with amyotrophic lateral sclerosis/frontotemporal dementia is translated to five dipeptide repeat proteins, among which poly-proline-arginine (PR) is the most toxic in cell and animal models, contributing to a variety of cellular defects. It has been proposed that polyPR disrupts nucleocytoplasmic transport (NCT) through several mechanisms including accumulation in the nuclear pore complex (NPC), accumulation in the nucleolus, and direct interactions with transport receptors. The NPC, which is the key regulator of transport between the cytoplasm and nucleus, plays a central role in these suggested mechanisms. Exploring polyPR interaction with the NPC provides valuable insight into the molecular details of polyPR-mediated NCT defects. To address this, we use coarse-grained molecular dynamics models of polyPR and the yeast NPC lined with intrinsically disordered FG-nucleoporins (FG-Nups). Our findings indicate no aggregation of polyPR within the NPC or permanent binding to FG-Nups. Instead, polyPR translocates through the NPC, following a trajectory through the central low-density region of the pore. In the case of longer polyPRs, we observe a higher energy barrier for translocation and a narrower translocation channel. Our study shows that polyPR and FG-Nups are mainly engaged in steric interactions inside the NPC with only a small contribution of specific cation-pi, hydrophobic, and electrostatic interactions, allowing polyPR to overcome the entropic barrier of the NPC in a size-dependent manner.