Biophysics

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 solid, 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 important study introduces a fully differentiable variant of the Gillespie algorithm as an approximate stochastic simulation scheme for complex chemical reaction networks, allowing kinetic parameters to be inferred from empirical measurements of network outputs using gradient descent. The concept and algorithm design are convincing and innovative. While the proofs of concept are promising, some questions are left open about implications for more complex systems that cannot be addressed by existing methods. This work has the potential to be of significant interest to a broad audience of quantitative and synthetic biologists.

eLife Assessment

This important study reports a detailed computational analysis of the CFTR ion channel's permeation mechanism, advancing our understanding of its structure-function relationship. The conclusions are based on extensive molecular dynamics simulations and thorough analysis, but the use of an approximate chloride ion model, known to underestimate key ion-protein interactions, leaves them incomplete without experimental or alternative computational validation. The work will be of interest to biophysicists working on CFTR and cystic fibrosis.

eLife Assessment

Rennert et al. developed a valuable thermodynamic framework to study the force response of branched actin networks from the crucial and unexplored perspective of energetic cost. They used the fact that the entropy production rate must be positive to derive inequalities that set limits on the maximum force produced by branched actin networks, and speculate that the dissipative cost beyond that required to move the load may be necessary to maintain an adaptive steady state. This work is highly innovative, but remains incomplete until the hypotheses of the model are better justified and the conclusions about the dissipative cost of the system are better established.

eLife Assessment

This study addresses an important and longstanding question regarding the molecular mechanism of protein misfolding in Ig light chain (LC) amyloidosis (AL), a life-threatening condition. By combining advanced techniques, including small-angle X-ray scattering, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, the authors provide convincing evidence that the "H state" distinguishes amyloidogenic from non-amyloidogenic LCs. These findings not only offer novel insights into LC structural dynamics but also hold promise for guiding therapeutic strategies in amyloidosis and will be of particular interest to structural biologists, biophysicists, and many others working on amyloid diseases.

eLife Assessment

This work uses enhanced sampling molecular dynamics methods to generate potentially useful information about a conformational change (the DFG flip) that plays a key role in regulating kinase function and inhibitor binding. The focus of the work is on the mechanism of conformational change and how mutations affect the transition. The evidence supporting the conclusions is incomplete.

eLife Assessment

The authors present a useful agent-based model to study the tensile force generated by myosin mini-filaments in actin systems (bundles and networks); by numerically solving a mechanical model of myosin-II filaments, the authors provide insights into how the geometry of the molecular components and their elastic responses determine the force production. This work is of interest to biophysicists (in particular theoreticians) investigating force generation of motor molecules from a biomechanical engineering and physics perspective. The authors convincingly show that cooperative effects between multiple myosin filaments can enhance the total force generated, but not the efficiency of force generation (force per myosin) if passive cross-linkers are present. This work would benefit from a more extensive discussion of the relevance of the results in view of the existing experimental literature.

eLife Assessment

The authors report how a previously published method, ReplicaDock, can be used to improve predictions from AlphaFold-multimer (AFm) for protein docking studies. The level of improvement is modest for cases where AFm is successful; for cases where AFm is not as successful, the improvement is more significant, although the accuracy of prediction is also notably lower. The evidence for the ReplicaDock approach being more predictive than AFm is particularly convincing for the antibody-antigen test case. Overall, the study makes a valuable contribution by combining data- and physics-driven approaches.

eLife Assessment

This manuscript describes a fundamental investigation of the functioning of Cas9 and in particular on how variant xCas9 expands DNA targeting ability by an increase-flexibility mechanism. The authors provide compelling evidence to support their mechanistic models and the relevance of flexibility and entropy in recognition. This work can be of interest to a broad community of structural biophysicists, computational biologists, chemists, and biochemists.

eLife Assessment

This study provides important computational insights into the dynamics of PROTAC-induced degradation complexes, offering a convincing demonstration that differences in degradation efficacy can be linked to linker properties. The analyses address reproducibility considerations comprehensively, reinforcing the study's conclusions. Overall, these findings are significant for advancing cancer treatments and will be of broad interest to both biochemists and biophysicists.