Biophysics

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

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

1. Aivaras Vaškevičius
2. Denis Baronas
3. Janis Leitans
4. Agnė Kvietkauskaitė
5. Audronė Rukšėnaitė
6. Elena Manakova
7. Zigmantas Toleikis
8. Algirdas Kaupinis
9. Andris Kazaks
10. Marius Gedgaudas
11. Aurelija Mickevičiūtė
12. Vaida Juozapaitienė
13. Helgi B Schiöth
14. Kristaps Jaudzems
15. Mindaugas Valius
16. Kaspars Tars
17. Saulius Gražulis
18. Franz-Josef Meyer-Almes
19. Jurgita Matulienė
20. Asta Zubrienė
21. Virginija Dudutienė
22. Daumantas Matulis

• Curated by eLife

  eLife Assessment

  This paper reports the synthesis of covalent inhibitors bearing a unique fragment as a protected covalent warhead for irreversible binding to histidine in carbonic anhydrase (CA) enzymes. These findings are important due to the broad utility of the approach for covalent drug discovery applications and could have long-term impacts on related covalent targeting approaches. The data convincingly support the main conclusions of the paper.

Reviewed by eLife

CTFFIND5 provides improved insight into quality, tilt, and thickness of TEM samples

1. Johannes Elferich
2. Lingli Kong
3. Ximena Zottig
4. Nikolaus Grigorieff

• Curated by eLife

  eLife Assessment

  This valuable work presents the latest version of CTFFIND, which is the most popular software for determination of the contrast transfer function (CTF) in cryo-electron microscopy. CTFFIND5 estimates and considers acquisition geometry and sample thickness, which leads to improved CTF determination. The paper describes compelling evidence that CTFFIND5 finds better CTF parameters than previous methods, in particular for tilted samples (e.g. for cryo-electron tomography) or where thickness is an issue (e.g. cellular samples, or electron microscopy at low voltages).

Reviewed by eLife

Ligand-coupled conformational changes in a cyclic nucleotide-gated ion channel revealed by time-resolved transition metal ion FRET

1. Pierce Eggan
2. Sharona E Gordon
3. William N Zagotta

• Curated by eLife

  eLife Assessment

  This valuable study uses fluorescence lifetime imaging and steady-state and time-resolved transition metal ion FRET to characterize conformational transitions in the isolated cyclic nucleotide binding domain of a bacterial CNG channel. The data are compelling and support the authors' conclusions. The results advance the understanding of allosteric mechanisms in CNBD channels and have theoretical and practical implications for other studies of protein allostery. A limitation is that only the cytosolic fragments of the channel were studied.

Reviewed by eLife

FLIMPA: A Versatile Software for Fluorescence Lifetime Imaging Microscopy Phasor Analysis

1. Sofia Kapsiani
2. Nino F. Läubli
3. Edward N. Ward
4. Mona Shehata
5. Clemens F. Kaminski
6. Gabriele S. Kaminski Schierle

Reviewed by Arcadia Science

Biophysical limits of ultrafast cellular motility

1. Ray Chang
2. Manu Prakash

Reviewed by Arcadia Science

The interplay between biomolecular assembly and phase separation

1. Giacomo Bartolucci
2. Ivar S Haugerud
3. Thomas CT Michaels
4. Christoph A Weber

• Curated by eLife

  eLife Assessment

  The authors present an important theoretical framework that describes the interplay between liquid-liquid phase separation and protein aggregation within a mean-field model. This work will be of high interest to the biophysics and molecular biology communities, as it will help understand and analyse assembly within biomolecular condensates in cells or in-vitro. Major strengths of this convincing work are the consideration of aggregates with various dimensionality and the possibility for protein gelation.

Reviewed by eLife

Phosphorylation regulated conformational diversity and topological dynamics of an intrinsically disordered nuclear receptor

1. Vasily Akulov
2. Alba Jiménez Panizo
3. Eva Estebanez Perpiña
4. John van Noort
5. Alireza Mashaghi

Reviewed by Arcadia Science

An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein

1. Sneha Menon
2. Subinoy Adhikari
3. Jagannath Mondal

• Curated by eLife

  eLife Assessment

  This study describes the application of machine learning and Markov state models to characterize the binding mechanism of alpha-Synuclein to the small molecule Fasudil. The results suggest that entropic expansion can explain such binding. However, the simulations and analyses in their present form are inadequate.

Reviewed by eLife

Direct and indirect salt effects on homotypic phase separation

1. Matt MacAinsh
2. Souvik Dey
3. Huan-Xiang Zhou

• Curated by eLife

  eLife Assessment

  In this potentially important study, the authors conducted atomistic simulations to probe the salt-dependent phase separation of the low-complexity domain of hnRN-PA1 (A1-LCD). The authors have identified both direct and indirect mechanisms of salt modulation, provided explanations for four distinct classes of salt dependence, and proposed a model for predicting protein properties from amino acid composition. There is a range of opinions regarding the strength of evidence, with some considering the evidence as incomplete due to the limitations in the length and statistical errors of the computationally intense atomistic MD simulations.

Reviewed by eLife