Structural Biology and Molecular Biophysics

eLife assessment

In this useful study, the authors show that N-acetylation of synuclein increases clustering of synaptic vesicles in vitro and that this effect is mediated by enhanced interaction with lysophosphatidylcholine. While the evidence for enhanced clustering is largely solid, the biological significance remains unclear.

eLife assessment

This study provides valuable information on the mechanism of PepT2 through enhanced-sampling molecular dynamics, backed by cell-based assays, highlighting the importance of protonation of selected residues for the function of a proton-coupled oligopeptide transporter (hsPepT2). The molecular dynamics approaches are convincing, but with limitations that could be addressed in the manuscript, including lack of incorporation of a protonation coordinate in the free energy landscape, possibility of protonation of the substrate, errors with the chosen constant pH MD method for membrane proteins, dismissal of hysteresis emerging from the MEMENTO method, and the likelihood of other residues being affected by peptide binding. Some changes to the presentation could be considered, including a better description of pKa calculations and the inclusion of error bars in all PMFs. Overall, the findings will appeal to structural biologists, biochemists, and biophysicists studying membrane transporters.

eLife assessment

This important study uses cellular automata and evolution algorithms to offer an alternative to long-range signalling models of developmental patterning. The computational evidence that local rules suffice to produce a robust and global pattern is convincing. With some additional insights that connect the theoretical findings back to real biological examples, this work could be of interest to the broad community of developmental and systems biologists.

eLife assessment

This study explores the physical principles underlying fluid flow and luminal transport within the endoplasmic reticulum; its important contribution is to highlight the strong physical constraints imposed by viscous dissipation in nanoscopic tubular networks. In particular, the work presents convincing evidence that commonly discussed mechanisms such as tubular contraction are unlikely to be at the origin of the observed transport velocities. As this study is solely theoretical and concerned with order of magnitude estimates, its main conclusions await experimental validation. The work will be of relevance to cell biologists and physicists interested in organelle dynamics.

eLife assessment

This elegant study presents important findings into how small molecules that were originally developed to inhibit the oncogenic kinase, BRAF, instead trigger activation of this kinase target. Compelling and comprehensive evidence supports a new allosteric model to explain the paradoxical activation. This rigorous work will be of great interest to biochemists, structural biologists, and those working on strategies to inhibit kinases in the context of human disease.

eLife assessment

This study provides important biophysical insights into the molecular mechanism underlying the association of alpha-synuclein chains, which is essential for understanding the pathogenesis of Parkinson's disease. The data analysis is solid, and the methodology can help investigate other molecular processes involving intrinsically disordered proteins. The benchmarking of the cgMD simulations should be improved to give the reader greater confidence in the conclusions presented.

eLife assessment

This study presents a valuable finding on the structural role of glycosylation at position N343 of the SARS-CoV-2 spike protein's receptor-binding domain in maintaining its stability, with implications across different variants of concern. The evidence supporting the claims of the authors is solid, although a more complete discussion of published data would have strengthened the study by providing a foundation for the new findings. The work will be of interest to evolutionary virologists.

eLife assessment

This is a very strong, well-written, and interesting paper analyzing in an original way how tension pattern dynamics can reveal the contribution of active versus passive intercalation during tissue elongation. The authors apply a new concept of isogonal tension decomposition to extract a global map of tissue mechanics that will be extremely valuable in the field of biomechanics. The model is convincing to explain the authors' data but could be strengthened further by analyzing data from mutant backgrounds that could serve as a test.

eLife assessment

This important study describes the new observation that nuclear volume responds to confinement in a manner that requires transit through mitosis. The authors present solid evidence demonstrating that nuclear volume decreases upon nuclear envelope reformation under confinement in a manner that reestablishes a homeostatic state of nuclear envelope tension. Additional experimental support could provide a more complete case for the proposed underlying mechanisms governing this response. The work will be of broad interest to cell biologists and those interested in cell and organismal scaling.

eLife assessment

This important study combines a range of biophysical techniques to carry out a series of compelling experiments to explore whether glutamine binding protein binds glutamine via an induced fit or a conformational selection process. The evidence supporting the major conclusion of the work is convincing, although it may not be generalized to other protein-ligand or protein-protein systems. The work will be of broad interest to biochemists and biophysicists.

eLife assessment

This important work illuminates the dynamics of BRAF in both its monomeric and dimeric forms, with or without inhibitors, combining traditional techniques and sophisticated computational analyses. The evidence presented is convincing, though a more detailed description of the analyses could enhance reproducibility and the quality of the results. This study will interest structural biologists, medicinal chemists, and pharmacologists.

eLife assessment

This study presents important methodologies for repeated brain ultrasound localization microscopy (ULM) in awake mice and a set of results indicating that wakefulness reduces vascularity and blood flow velocity. The efficiency of the technique is however incompletely demonstrated, in particular regarding the reliability of longitudinal imaging. This study is relevant for scientists investigating vascular physiology in the brain.

eLife assessment

In this interesting study, Drożdżyk and colleagues analyze the ability of placental CALHM orthologs to form stable complexes, identifying that CALHM2 and CALHM4 form heterooligomeric channels. The authors then determine cryo-EM structures of heterooligomeric CALHM2 and CALHM4 that reveal a distinct arrangement in which the two orthologs can interact, but preferentially segregate in the channel. This is an important study; the data provide compelling support for the interpretations and overall, the work is clearly described.

eLife assessment

This manuscript reports important data on the stability of nucleosomes with dsDNA substrates containing defined mismatches at three defined nucleosomal positions. Compelling evidence obtained by single-molecule FRET experiments shows that certain mismatches lead to more stable nucleosomes likely because mismatches kink to enhance DNA flexibility leading to higher nucleosome stability. The biological significance and implications of the findings remain unclear.

eLife assessment

Pin1 as an essential prolyl cis/trans isomerase has attracted considerable attention because this enzyme family is implicated in cancer and neurodegenerative diseases. However, the requirement for its catalytic function remains a matter of dispute. The authors provide solid evidence that Pin1 modulates the activity of an important cell signaling kinase, Protein Kinase C, by a non-catalytic mechanism, acting as a chaperone to regulate the stability of this kinase.

eLife assessment:

The study answers the important question of whether the conformational dynamics of proteins are slaved by the motion of solvent water or are intrinsic to the polypeptide. The results from neutron scattering experiments, involving isotopic labelling, carried out on a set of four structurally different proteins are convincing, showing that protein motions are not coupled to the solvent. A strength of this work is the study of a set of proteins using spectroscopy covering a range of resolutions, however, it suffers from some scholarly shortcomings and limited discussion of results. The work is of broad interest to researchers in the fields of protein biophysics and biochemistry.

eLife assessment

This manuscript claims to have found evidence for coordinated membrane potential oscillations in E. coli biofilms that can be linked to a putative K+ channel and that may serve to enhance photo-protection. The finding of waves of membrane potential would be of interest to a wide audience from molecular biology to microbiology and physical biology. Unfortunately, a major issue with the experimental technique affects the interpretation of the observations: the dye used has been previously shown not to report membrane potential, leaving the evidence inadequate.

eLife assessment

This study makes a valuable finding, a polyunsaturated fatty acid increases the conductance of a K+ channel by helping its K+ selectivity filter form a conductive state. Overall, support for this major claim is solid, though other claims remain speculative with incomplete support. These findings are expected to be of interest to researchers studying ion channel gating.

eLife assessment

This study presents a useful comparison of the dynamic properties of two RNA-binding domains. The data collection and analysis are solid, making excellent use of a suite of NMR methods. However, evidence to support the proposed model linking dynamic behavior to RNA recognition and binding by the tandem domains remains incomplete. The work will be of interest to biophysicists working on RNA-binding proteins.

eLife assessment

This important work significantly advances the field of computational modelling of genome organisation through the development of OpenNucleome. The evidence supporting the tool's effectiveness is compelling, as the authors compare their predictions with experimental data. It is anticipated that OpenNucleome will attract significant interest from the biophysics and genomics communities. Providing comprehensive tutorials and documentation is highly encouraged.