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Single-event completion times, such as are estimated in viral entry, offer both promise and challenge to kinetic interpretation. The promise is that they constrain underlying kinetic models much more efficiently than bulk kinetics, but the challenge is that completion times alone can incompletely determine complex reaction topologies. Gamma distributions or mechanistic models have often been used to estimate kinetic parameters for such data, but the gamma distribution relies on homogenous processes to explain the rate-limiting behavior of the system.

Controlling the physicochemical properties of nanoparticles is important for their performance as drug carriers, pharmaceuticals, or imaging contrast agents in nanomedicine. Predictive models can accelerate experimental designs at reduced time and costs compared to a brute-force approach conventionally used. However, physical principles underlying particle-cell interactions are still poorly understood due to their large size contrast, hindering the model development. In this work, we describe a model that examines the interaction between multiple particles and the membrane of a mammalian cell or an artificial vesicle, thus influencing the outcomes of surface adsorption, detachment or uptake of particles.

Gating-modifying peptide toxins, preferentially bind to the voltage-sensing domain KV4.3 voltage-gated potassium channels, the molecular determinant of this interaction remains unclear. Through unconstrained multiscale MD simulations, we could recapitulate spontaneous binding of gating-modifiyng toxin, such as SNX-482 (from tarantula Hysterocrates gigas) to KV4.3 potassium channel at the membrane interface, overcoming the limitations of traditional docking methods. This approach revealed two likely binding poses centered on the S3-S4 linker of KV4.3, one of which included pore region residues.

In biomembranes lipid mobility exhibits deviations from the classical diffusive behavior of Brownian particles, i.e. ‘anomalous’ diffusion. The question arises as to how this anomalous diffusive behavior varies in gel, ripple, and fluid biomembrane phases. In this study, we perform all-atom molecular dynamics (MD) simulations of dimyristoylphosphatidylcholine (DMPC) bilayers in the three different phases and analyze the results using the framework of the Generalized Langevin Equation (GLE). This analysis emphasizes sub-diffusive behavior on the relatively short, picosecond-nanosecond timescales, capturing local molecular constraints and transient caging effects during the crossover of atomic dynamics from vibrational to incipient anharmonic motion.

Electron diffraction of 3D microcrystals (3D ED/MicroED) is an emerging technique that uses electrons to determine proteins structure from their nano-sized 3D crystals, thus overcoming the limitations on crystal-size dimensions generally imposed by X-ray or neutron diffraction. The strong interactions of electrons with matter have the potential to reveal the location of light atoms (e.g., hydrogens), revealing interaction networks, and to provide information about the charge states of the atoms.

Protein misfolding can lead to protein malfunction, which may compromise cell viability. Chaperones, including the HSP70 system, are proteins that have evolved to restore the native structure of misfolded proteins. Although most chaperones, including DnaK (bacterial HSP70), were first described over 30 years ago, important questions related to their mechanisms remain unanswered. Only a small number of model proteins are used in the literature for misfolding and refolding studies. Previously, we described several NanoLuc (Nluc) luciferase-based constructs as models for DnaK-assisted chaperone refolding: Nluc2, Nluc3, and others, where the Nluc module was combined with the titin I91 domain.

The endoplasmic reticulum (ER) forms an elaborate contiguous network extending through the cytoplasm of eukaryotic cells. The ER is surrounded by a membrane that separates its lumen from the cytoplasm. The ER membrane harbors channels and pumps capable of controlling ion flux and creating a voltage gradient. Because the ER membrane potential is difficult to study experimentally little is known about how voltage influences its many vital functions. Here we introduce optical probes of ER membrane potential derived from the hybrid voltage sensor (hVoS) family of genetically-encoded voltage sensors.

To interact with their environment, living cells use active cytoskeletal forces to form dynamic membrane structures such as tubular filopodia and sheet-like lamellipodia. To understand the formation and dynamics of these structures, we perform non-equilibrium simulations of dynamically triangulated vesicles under constrained volume. We investigate vesicle shape remodeling driven by local effects of internal active filaments, as well as large-scale shape transformations resulting from volume changes controlled by the osmotic effect.

The SARS-CoV-2 nucleocapsid (N) protein is a primary target for diagnostic antibody-based detection of COVID-19. To enhance diagnostic accuracy and resilience against emerging variants, it is essential to map the binding sites of diagnostic antibodies. This study employs hydrogen-deuterium exchange mass spectrometry (HDX-MS) to identify the epitopes of diagnostic antibodies targeting the N protein. HDX-MS provides high-resolution insights into protein-antibody interactions by detecting changes in solvent accessibility and protein dynamics upon antibody binding.

Phosphorylation is a ubiquitous post-translational modification used across all domains of life to regulate protein stability, folding, subcellular localization, function, and activity. The most common targets of protein phosphorylation are the amino acids serine, threonine, and tyrosine. The considerable change in electrostatic character of these residues upon phosphorylation, from polar neutral to strongly negatively charged at physiological pH, implies a major change in biophysical properties of these residues.

Mechanical strain is a key contributor to mild traumatic brain injury (mTBI), yet the impact of varying strain magnitudes and strain rates on cellular function and disease remain poorly understood. In this study, we examined acute membrane damage responses to mechanical strain in SH-SY5Y cells and the modulatory roles of tau phosphorylation and microtubule stability in the context of mTBI. Using a custom cell stretching system, we found that increased MT stability, induced by paclitaxel, increases acute membrane damage, while MT depolymerization via nocodazole reduces it.

Fluorescent proteins (FPs) comprise hundreds of different genetically encoded biosensors. Anomalous FP photo-physics, consistent with excitonic coupling, i.e. delocalized excitation, has been previously reported. Since delocalized excitation can potentially alter fluorescence lifetimes, intensities, and spectra at long distances, its impact needs to be evaluated for the proper design and interpretation of biosensor experiments, as well as for the development of genetically encoded excitonic materials.