Biophysics

eLife Assessment

This manuscript describes a novel method for determining the mechanical parameters of the kinesin, KIF1A, that uses fluorescence microscopy and does not require an optical tweezer apparatus. The length of a tethered fluorescent DNA nanospring is measured as the kinesin moves processively along the microtubule and then stalls. The work reports important findings, and (barring a few exceptions) the evidence supporting the claims is generally convincing.

eLife Assessment

This study uses steered molecular dynamics simulations to interrogate force transmission in the mechanosensitive NOMPC channel, which plays roles including soft-touch perception, auditory function, and locomotion. The valuable finding that the ankyrin spring transmits force through torsional rather than compression forces may help understand the entire TRP channel family. The evidence is considered to be solid, although full opening of the channel is not seen, and it has been noted that experimental validation of reduced mechanosensitivity through mutagenesis of proposed ankyrin/TRP domain coupling interactions would help substantiate the findings.

eLife Assessment

This important study uses advanced computational methods to elucidate how environmental dielectric properties influence the interaction strengths of tyrosine and phenylalanine in biomolecular condensates. The evidence supporting the claims of the authors is convincing, as the simulations are performed rigorously providing mechanistic insights into the origin of the differences between the two aromatic amino acids considered. This study will be of broad interest to researchers studying biomolecular phase separation.

eLife Assessment

This valuable study presents an analysis of evolutionary conservation in intrinsically disordered regions, identified as key drivers of phase separation, leveraging a protein language model. The strength of evidence presented is convincing overall, though the theoretical grounding could benefit from further development.

eLife Assessment

This important study presents a sequence-based method for predicting drug-interacting residues in intrinsically disordered proteins (IDPs), addressing a significant challenge in understanding small-molecule:IDP interactions. The findings have solid support through examples underscoring the role of aromatic interactions. While predicted binding sites remain coarse, validation was done on a total of 10 IDPs at varying depths. The method builds on the authors' previous work and, with ad hoc modifications, is poised to benefit this emerging field.

eLife Assessment

This study offers a valuable theoretical framework for quantifying molecular transport across interfaces between coexisting liquid phases, emphasizing interfacial resistance as a central factor governing transport kinetics. The mathematical derivations are solid. To enhance the paper's relevance and broaden its appeal, it would be helpful to clarify how the key equations connect to existing literature and to elucidate the physical mechanisms underlying scenarios that give rise to substantial interfacial resistance.

eLife Assessment

This valuable paper investigates how fish avoid thermal disturbances that occur on fast timescales. The authors use a creative experimental approach that quickly creates a vertical thermal interface, which they combine with careful behavioral analyses. The evidence supporting their results is solid, but there is a potential confounding factor between temperature and vertical positioning, and characterization of the thermal interface would greatly assist in interpreting the results.

eLife Assessment

This valuable study investigates the self-assembly activity of death-fold domains. The data collected using advanced microscopy and distributed amphifluoric FRET-based flow cytometry methods provide solid evidence for the conclusions, although the interpretations based on these conclusions remain speculative in some cases. This paper is broad interest to those studying a variety of biological pathways involved in inflammatory responses and various forms of cell death.

eLife Assessment

This important study combines imaginative and innovative experiments with a finite element modelling to demonstrate the relevance of poroelasticity in the mechanical properties of cells across physiologically relevant time and length scales. The authors present convincing evidence that cytosolic flows and pressure gradients can persist in cells with permeable membranes, generating spatially segregated influx and outflux zones. These findings are of interest to the cell biology and biophysics communities.

eLife Assessment

This manuscript presents useful insights into the molecular basis underlying the positive cooperativity between the co-transported substrates (galactoside sugar and sodium ion) in the melibiose transporter MelB. Building on years of previous studies, this work improves on the resolution of previously published structures and reports the presence of a water molecule in the sugar binding site that would appear to be key for its recognition, introduces further structures bound to different substrates, and utilizes HDX-MS to further understand the positive cooperativity between sugar and the co-transported sodium cation. Although the experimental work is solid, the presentation of the data lacks clarity, and in particular, the HDX-MS data interpretation requires further explanation in both methodology and discussion, as well as a clearer description of the new insight that is obtained in relation to previous studies. The work will be of interest to biologists and biochemists working on cation-coupled symporters, which mediate the transport of a wide range of solutes across cell membranes.