Biophysics

Compound Mutations in the Abl1 Kinase Cause Inhibitor Resistance by Shifting DFG Flip Mechanisms and Relative State Populations

1. Gabriel Monteiro da Silva
2. Kyle Lam
3. David C Dalgarno
4. Brenda M Rubenstein

• Curated by eLife

  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.

Reviewed by eLife

Impacts of Structural Properties of Myosin II Filaments on Force Generation

1. Shihang Ding
2. Pei-En Chou
3. Shinji Deguchi
4. Taeyoon Kim

• Curated by eLife

  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.

Reviewed by eLife

Reliable protein–protein docking with AlphaFold, Rosetta, and replica exchange

1. Ameya Harmalkar
2. Sergey Lyskov
3. Jeffrey J Gray

• Curated by eLife

  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.

Reviewed by eLife

Flexibility in PAM recognition expands DNA targeting in xCas9

1. Kazi A Hossain
2. Lukasz Nierzwicki
3. Modesto Orozco
4. Jacek Czub
5. Giulia Palermo

• Curated by eLife

  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.

Reviewed by eLife

PROTAC-induced protein structural dynamics in targeted protein degradation

1. Kingsley Y Wu
2. Ta I Hung
3. Chia-en A Chang

• Curated by eLife

  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.

Reviewed by eLife

Tension-induced suppression of allosteric conformational changes explains coordinated stepping of kinesin-1

1. Tsukasa Makino
2. Ryo Kanada
3. Teppei Mori
4. Ken-ichi Miyazono
5. Yuta Komori
6. Haruaki Yanagisawa
7. Shoji Takada
8. Masaru Tanokura
9. Masahide Kikkawa
10. Michio Tomishige

Reviewed by Review Commons

Mechanical stresses govern myoblast fusion and myotube growth

1. Yoann Le Toquin
2. Sushil Dubey
3. Aleksandra Ardaševa
4. Lakshmi Balasubramaniam
5. Emilie Delaune
6. Valérie Morin
7. Amin Doostmohammadi
8. Christophe Marcelle
9. Benoît Ladoux

Reviewed by preLights

Cell cycle and age-related modulations of mouse chromosome stiffness

1. Ning Liu
2. Wenan Qiang
3. Philip W Jordan
4. John F Marko
5. Huanyu Qiao

• Curated by eLife

  eLife Assessment

  This valuable paper describes the stiffness of meiotic chromosomes in both oocytes and spermatocytes. The authors identify differences in stiffness between meiosis I and II chromosomes, as well as an age-dependent increase in stiffness in meiosis I (and meiosis II) chromosomes, results that are highly significant for the field of chromosome biology. The report is, however, mostly descriptive and the mechanisms underlying age-dependent changes in chromosome stiffness remain unclear. The evidence suggesting that changes in stiffness are independent of cohesin, which is known to deteriorate with age, is still incomplete.

Reviewed by eLife

Probing the force-from-lipid mechanism with synthetic polymers

1. Miranda L Jacobs
2. Jan Steinkühler
3. Audra Lemley
4. Megan J Larmore
5. Taylor F Gunnels
6. Leo CT Ng
7. Stephanie M Cologna
8. Paul G DeCaen
9. Neha P Kamat

• Curated by eLife

  eLife Assessment

  Gating of mechanosensitive channels has been explained by the force-from-lipids model in which mechanical coupling of the channel protein to the plasma membrane transfers force from membrane tension to open the channel. In this important manuscript, the authors provide evidence for this mechanism in two different mechanically gated channels. The experiments were carried out in the same membranes, but the evidence is incomplete without a clear explanation of the relationship between measured mechanical parameters and membrane interfacial tension.

Reviewed by eLife

Mechanistic insight for T-cell exclusion by cancer-associated fibroblasts in human lung cancer

1. Joseph Ackermann
2. Chiara Bernard
3. Philemon Sirven
4. Helene Salmon
5. Massimiliano Fraldi
6. Martine D Ben Amar

• Curated by eLife

  eLife Assessment

  This is a valuable report of a spatially-extended model to study the complex interactions between immune cells, fibroblasts, and cancer cells, providing insights into how fibroblast activation can influence tumor progression. The model opens up new possibilities for studying fibroblast-driven effects in diverse settings, which is crucial for understanding potential tumor microenvironment manipulations that could enhance immunotherapy efficacy. While the results presented are convincing and follow logically from the model's assumptions, some of these assumptions, as acknowledged by the authors, may oversimplify certain aspects in light of complex experimental findings, system geometry, and general principles of active matter research. Nonetheless, the authors provide justification for their work as a meaningful step towards more comprehensive modeling approaches.

Reviewed by eLife