Testing the feasibility of targeting a conserved region on the S2 domain of the SARS-CoV-2 spike protein Friday, March 15, 2024 The efficacy of vaccines against the SARS-CoV-2 virus significantly declines with the emergence of mutant strains, prompting investigation into the feasibility of targeting highly conserved but often cryptic regions on the S2 domain of spike protein. Using tools from molecular dynamics, we find that exposure of this conserved S2 epitope located in the central helices below the receptor binding domains would require large-scale motion beyond RBD up-down motion, but, along the reaction coordinates we explored, it is unlikely to be exposed by such large-scale dynamic fluctuations of the S1 domain without any external facilitating factors, in spite of some previous computational evidence suggesting transient exposure of this region. Read more
Governing principles of transcriptional logic out of equilibrium Thursday, March 14, 2024 To survive, adapt, and develop, cells respond to external and internal stimuli, by tightly regulating transcription. Transcriptional regulation involves the combinatorial binding of a repertoire of transcription factors (TFs) to DNA, which often results in switch-like binary outputs, akin to Boolean logic gates. Recent experimental studies have demonstrated that in eukaryotes, transcription factor binding to DNA often involves energy expenditure, thereby driving the system out of equilibrium. The governing principles of transcriptional logic operations out of equilibrium remain unexplored. Read more
Bending of a Lipid Membrane Edge by Annexin A5 Trimers Thursday, March 14, 2024 Plasma membrane damage occurs in healthy cells and more frequently in cancer cells where high growth rates and metastasis result in frequent membrane damage. The annexin family of proteins plays a key role in membrane repair. Annexins are recruited at the membrane injury site by Ca+2, and repair the damaged membrane in concert with several other proteins. Annexin A4 and Annexin A5 (ANXA5) form trimers at the bilayer surface, and previous simulations show that the trimers induce high local negative membrane curvature on a flat bilayer. Read more
Calculation of Protein-Ligand Binding Entropies Using a Rule-Based Molecular Fingerprint Wednesday, March 13, 2024 The use of fast in silico prediction methods for protein-ligand binding free energies holds significant promise for the initial phases of drug development. Numerous traditional physics-based models (e.g., implicit solvent models), however, tend to either neglect or heavily approximate entropic contributions to binding due to their computational complexity. Consequently, such methods often yield imprecise assessments of binding strength. Machine learning (ML) models provide accurate predictions and can often outperform physics-based models. Read more
Investigating the ERG a-wave and Retinal Diseases with Rod Equivalent Circuit Model Based on the APD Tuesday, March 12, 2024 Most empirically supported mathematical models of rod cells lack theoretical support from actual physical devices. Therefore, this paper proposes an equivalent circuit model for the rod is proposed based on the photoconductive properties of the avalanche photodetector (APD) and combined with the electrical properties of the rod. The model employs the photodetector to simulate the source of the photocurrent in outer segments of rod cells and takes into account the electrical properties of the inner and outer segments, the nucleus, and the synaptic terminals. Read more
Lipid droplets as substrates for protein phase separation Saturday, March 9, 2024 Membrane-associated protein phase separation plays critical roles in cell biology, driving essential cellular phenomena from immune signaling to membrane traffic. Importantly, by reducing dimensionality from three to two dimensions, lipid bilayers can nucleate phase separation at far lower concentrations compared to those required for phase separation in solution. How might other intracellular lipid substrates, such as lipid droplets, contribute to nucleation of phase separation? Distinct from bilayer membranes, lipid droplets consist of a phospholipid monolayer surrounding a core of neutral lipids, and they are energy storage organelles that protect cells from lipotoxicity and oxidative stress. Read more
The open channel state in anion channelrhodopsin GtACR1 is a red-absorbing intermediate. Saturday, March 9, 2024 Anion channelrhodopsin GtACR1 is a powerful optogenetic tool to inhibit nerve activity. Its kinetic mechanism was interpreted in terms of the bacteriorhodopsin photocycle and the L intermediate was assigned to the open channel state. Here we report the results of the comparison between the time dependence of the channel currents and the time evolutions of the K-like and L-like spectral forms. Based on the results we question the current view on GtACR1 kinetics and the assignment of the L intermediate to the open channel state. Read more
The ATPase Asymmetry: Novel Computational Insight into Coupling Diverse FO Motors with Tripartite F1 Friday, March 8, 2024 ATP synthase, a crucial enzyme for cellular bioenergetics, operates via the coordinated coupling of a FO motor, which presents variable symmetry, and a tripartite F1 motor. Despite extensive research, the understanding of their coupling dynamics, especially with non-10-fold symmetrical FO motors, remains incomplete. This study investigates the coupling patterns between 8- and 9-fold FO motors and the constant 3-fold F1 motor using coarse-grained molecular dynamics (MD) simulations. We unveil that in the case of a 9-fold FO motor, a 3-3-3 motion is most likely to occur, while a 3-3-2 motion predominates with an 8-fold FO motor. Read more
Coupling of zinc and GTP binding drives G-domain folding in Acinetobacter baumannii ZigA Friday, March 8, 2024 COG0523 proteins, also known as nucleotide-dependent metallochaperones, are a poorly understood class of small P-loop G3E GTPases. Multiple family members play critical roles in bacterial pathogen survival during an infection as part of the adaptive response to host-mediated “nutritional immunity.” Our understanding of the structure, dynamics, and molecular-level function of COG0523 proteins, apart from the eukaryotic homologue, Zng1, remains in its infancy. Here, we use X-ray absorption spectroscopy to establish that Acinetobacter baumannii (Ab) ZigA coordinates ZnII using all three cysteines derived from the invariant CXCC motif to form an S3(N/O) coordination complex, a feature inconsistent with an available ZnII-bound crystal structure of a distantly related COG0523 protein of unknown function from E. Read more
Mitigating Transcription Noise Via Protein Sharing in Syncytial Cells Friday, March 8, 2024 Bursty transcription allows nuclei to concentrate the work of transcribing mRNA into short, intermittent intervals, potentially reducing transcriptional interference. However, bursts of mRNA production can increase noise in protein abundances. Here we formulate models for gene expression in syncytia, or multinucleate cells, showing that protein abundance noise may be mitigated locally via spatial averaging of diffuse proteins. Our modeling shows a universal reduction in protein noise, that increases with the average number of nuclei per cell, and persists even when the number of nuclei is itself a random variable. Read more