Biophysics

Discovery of a heparan sulfate binding domain in monkeypox virus H3 as an anti-poxviral drug target combining AI and MD simulations

1. Bin Zheng
2. Meimei Duan
3. Yifen Huang
4. Shangchen Wang
5. Jun Qiu
6. Zhuojian Lu
7. Lichao Liu
8. Guojin Tang
9. Lin Cheng
10. Peng Zheng

• Curated by eLife

  eLife Assessment

  This work presents important findings regarding the interaction of the monkeypox virus (MPXV) attachment H3 protein with the cellular receptor heparan sulfate and the use of this information to develop antivirals potentially effective against all orthopoxviruses. Using a combination of state-of-the art computational and wet experiments the authors present convincing evidence to sustain their claims. These results will interest those working on basic orthopoxviruses biology and antiviral development.

Reviewed by eLife

Atomic-Level Free Energy Landscape Reveals Cooperative Symport Mechanism of Melibiose Transporter

1. Ruibin Liang
2. Lan Guan

• Curated by eLife

  eLife Assessment

  In this potentially important study, the authors employed advanced computational techniques to explore a detailed atomistic description of the mechanism and energetics of substrate translocation in the MelB transporter. The overall approach is solid and reveals the coupling between sodium binding and melibiose transport through a series of conformational transitions, and the results for a mutant are also in qualitative agreement with the experiment, providing further support to the computational analyses. Nevertheless, the level of evidence is considered incomplete since there are concerns regarding the convergence and initial guess of the string calculations, leaving doubts that the computed pathway does not reflect the most energetically favorable mechanism.

Reviewed by eLife

A direct computational assessment of vinculin-actin unbinding kinetics reveals catch bonding behavior

1. Willmor J Peña Ccoa
2. Fatemah Mukadum
3. Aubin Ramon
4. Guillaume Stirnemann
5. Glen M Hocky

Reviewed by PREreview

Interplay of condensate material properties and chromatin heterogeneity governs nuclear condensate ripening

1. Deb Sankar Banerjee
2. Tafadzwa Chigumira
3. Rachel M Lackner
4. Josiah C Kratz
5. David M Chenoweth
6. Shiladitya Banerjee
7. Huaiying Zhang

• Curated by eLife

  eLife Assessment

  In this potentially valuable study, the authors employed in vivo experiments and theoretical modeling to study the growth dynamics of nuclear condensates. They observed that condensates can exhibit distinct growth modes, as dictated by the competition between condensate surface tension and local elasticity of chromatin. While the theoretical model appears to capture the experimental observations, the level of evidence supporting the proposed growth mechanism is incomplete due to, among other limitations, the multiple fitting parameters and poorly justified Neo-Hookean elasticity.

Reviewed by eLife

Determining accurate conformational ensembles of intrinsically disordered proteins at atomic resolution

1. Kaushik Borthakur
2. Thomas R. Sisk
3. Francesco P. Panei
4. Massimiliano Bonomi
5. Paul Robustelli

Reviewed by PREreview

Ab initio prediction of specific phospholipid complexes and membrane association of HIV-1 MPER antibodies by multi-scale simulations

1. Colleen A Maillie
2. Kiana Golden
3. Ian A Wilson
4. Andrew B Ward
5. Marco Mravic

• Curated by eLife

  eLife Assessment

  This valuable study reports multi-scale molecular dynamics simulations to investigate a class of highly potent antibodies that simultaneously engage with the HIV-1 Envelope trimer and the viral membrane. The work provides insights into how broadly neutralizing antibodies associate with lipids proximal to membrane-associated epitopes to drive neutralization. After extensive revision, the level of evidence is considered solid, although a quantitative assessment of the underlying energetics remain difficult to obtain.

Reviewed by eLife

Molecular dynamics simulations illuminate the role of sequence context in the ELF3-PrD-based temperature sensing mechanism in plants

1. Richard J Lindsay
2. Rafael Giordano Viegas
3. Vitor BP Leite
4. Philip A Wigge
5. Sonya M Hanson

• Curated by eLife

  eLife Assessment

  In this potentially valuable computational study, the authors conducted atomistic and coarse-grained simulations to probe the temperature-dependent phase behaviors of ELF3, a disordered component of the evening complex in plant. The results aim to highlight the role of polyQ tracts in modulating the temperature sensitivity. The level of evidence is considered incomplete, due to the lack of systematic calibration of the coarse-grained model and limited statistical uncertainty analysis, especially considering the relatively subtle nature of the differences due to temperature change.

Reviewed by eLife

Motor clustering enhances kinesin-driven vesicle transport

1. Rui Jiang
2. Qingzhou Feng
3. Daguan Nong
4. You Jung Kang
5. David Sept
6. William O. Hancock

Reviewed by preLights

Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration

1. Debabrata Dey
2. Shir Marciano
3. Anna Poryval
4. Ondřej Groborz
5. Lucie Wohlrabova
6. Tomás Slanina
7. Gideon Schreiber

• Curated by eLife

  eLife Assessment

  This is a valuable study on the diffusion rates of drug molecules in human-derived cells, presenting convincing data indicating that their diffusion behavior depends on their charged state. It proposes that blocking drug protonation enhances diffusion and fractional recovery, suggesting improved intracellular availability of weakly basic drugs. The findings are significant for drug design and understanding the biophysical behavior of small molecules in cells.

Reviewed by eLife

Conformational dynamics of a nicotinic receptor neurotransmitter site

1. Mrityunjay Singh
2. Dinesh C Indurthi
3. Lovika Mittal
4. Anthony Auerbach
5. Shailendra Asthana

• Curated by eLife

  eLife Assessment

  This useful work provides insight into agonist binding to nicotinic acetylcholine receptors, which is the stimulus for channel activation that regulates muscle contraction at the neuromuscular junction. The authors use in silico methods to explore the transient conformational change from a low to high affinity agonist-bound conformation as occurs during channel opening, but for which structural information is lacking owing to its transient nature. The simulations indicating that ligands flip ~180 degrees in the binding site as it transitions from a low to high affinity bound conformation are solid. A limitation is the approximation of binding energies using Poisson-Boltzmann Surface Area and mismatch between calculated and experimental binding energies for two of the four ligands tested. Nonetheless, this work presents an intriguing picture for the nature of a transient conformational change at the agonist binding site correlated with channel opening.

Reviewed by eLife