Biophysics

Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond

1. Márton A Simon
2. László Csanády

• Curated by eLife

  Evaluation Summary:

  Multiple inherited mutations in the epithelial CFTR anion-permeable channel cause cystic fibrosis through different molecular mechanisms that can be targeted by different types of drugs to treat the disease. Drawing from available structural information and double-mutant cycle analysis of patch-clamp recordings, Simon and Csanády find that one of the most common CFTR disease-causing mutations, R117H, disrupts an interaction between the R117 side-chain and a main-chain carbonyl that selectively stabilizes the open state of the channel. These findings may open new paths of exploration for treating patients carrying this mutation, and provide important mechanistic constraints towards understanding the gating mechanism of CFTR proteins.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Reviewed by eLife

Probing the mutational landscape of the SARS-CoV-2 spike protein via quantum mechanical modeling of crystallographic structures

1. Marco Zaccaria
2. Luigi Genovese
3. William Dawson
4. Viviana Cristiglio
5. Takahito Nakajima
6. Welkin Johnson
7. Michael Farzan
8. Babak Momeni

Reviewed by ScreenIT

Label-free imaging of M1 and M2 macrophage phenotypes in the human dermis in vivo using two-photon excited FLIM

1. Marius Kröger
2. Jörg Scheffel
3. Evgeny A Shirshin
4. Johannes Schleusener
5. Martina C Meinke
6. Jürgen Lademann
7. Marcus Maurer
8. Maxim E Darvin

• Curated by eLife

  Evaluation Summary:

  Kröger et al use 2-photon FLIM tomography to perform correlative imaging on in vitro, ex vivo and in vivo blood and skin cells to determine characteristic NADPH fluorescence lifetimes for M1 and M2 ends of macrophage spectrum. Interestingly, M1 and M2 macrophages, and all other tissue cells, had distinctive lifetime features leading to robust prediction of phenotypes, with ground trust defined by cytokine staining. They generate a decision tree that has ~90% accuracy in identifying M1 and M2 based on FLIM parameters and additional information. The ability to use two photon fluorescence lifetime tomography of NADPH fluorescence to identify macrophages and their inflammatory status in human tissues should open opportunities in experimental medicine and eventually medical diagnosis.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife

The versatile regulation of K2P channels by polyanionic lipids of the phosphoinositide and fatty acid metabolism

1. Elena B. Riel
2. Björn C. Jürs
3. Sönke Cordeiro
4. Marianne Musinszki
5. Marcus Schewe
6. Thomas Baukrowitz

Reviewed by Biophysics Colab

Allosteric modulation of the adenosine A2A receptor by cholesterol

1. Shuya Kate Huang
2. Omar Almurad
3. Reizel J Pejana
4. Zachary A Morrison
5. Aditya Pandey
6. Louis-Philippe Picard
7. Mark Nitz
8. Adnan Sljoka
9. R Scott Prosser

• Curated by eLife

  Evaluation Summary:

  Cholesterol has long been known to have significant effects on G protein-coupled receptor (GPCR) ligand binding properties and stability, and cholesterol/GPCR interactions have frequently been observed in high-resolution structures. However, relatively limited biophysical work has been done to investigate the mechanistic basis for cholesterol's effects. This manuscript describes the use of a sensitive 19F NMR probe to monitor conformational equilibria in a prototypical GPCR, the A2a adenosine receptor. These experiments, together with data from other NMR experiments, computational analysis, and G protein assays, show that the subtle effects of cholesterol derive in large part from modulation of membrane biophysical properties, in contrast to conventional allosteric modulators that exert their effects through direct long-lived receptor binding.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Reviewed by eLife

pH-dependent 11° F1FO ATP synthase sub-steps reveal insight into the FO torque generating mechanism

1. Seiga Yanagisawa
2. Wayne D Frasch

• Curated by eLife

  Evaluation Summary:

  This paper is of outstanding interest to the broad community of scientists interested in biological energy conversion in general and rotary ATPases in particular. The authors show that the 36{degree sign} power stroke in ATP synthesis is subdivided into two steps of 11{degree sign} and 25{degree sign} in the E. coli enzyme, which serves as a comparatively simple model of the fundamental and universally important process of ATP production in mitochondria and chloroplasts. By combining precise and sophisticated single-molecule studies with directed mutagenesis, this work provides the much-needed functional context for recent high-resolution cryo-EM structures of rotary ATPases.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Reviewed by eLife

#COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol

1. Abigail Dommer
2. Lorenzo Casalino
3. Fiona Kearns
4. Mia Rosenfeld
5. Nicholas Wauer
6. Surl-Hee Ahn
7. John Russo
8. Sofia Oliveira
9. Clare Morris
10. Anthony Bogetti
11. Anda Trifan
12. Alexander Brace
13. Terra Sztain
14. Austin Clyde
15. Heng Ma
16. Chakra Chennubhotla
17. Hyungro Lee
18. Matteo Turilli
19. Syma Khalid
20. Teresa Tamayo-Mendoza
21. Matthew Welborn
22. Anders Christensen
23. Daniel GA Smith
24. Zhuoran Qiao
25. Sai K Sirumalla
26. Michael O’Connor
27. Frederick Manby
28. Anima Anandkumar
29. David Hardy
30. James Phillips
31. Abraham Stern
32. Josh Romero
33. David Clark
34. Mitchell Dorrell
35. Tom Maiden
36. Lei Huang
37. John McCalpin
38. Christopher Woods
39. Alan Gray
40. Matt Williams
41. Bryan Barker
42. Harinda Rajapaksha
43. Richard Pitts
44. Tom Gibbs
45. John Stone
46. Daniel M. Zuckerman
47. Adrian J. Mulholland
48. Thomas Miller
49. Shantenu Jha
50. Arvind Ramanathan
51. Lillian Chong
52. Rommie E Amaro

Reviewed by ScreenIT

Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2

1. Mohammad Afsar
2. Rohan Narayan
3. Md Noor Akhtar
4. Deepakash Das
5. Huma Rahil
6. Santhosh Kambaiah Nagaraj
7. Sandeep M Eswarappa
8. Shashank Tripathi
9. Tanweer Hussain

• Curated by eLife

  Evaluation Summary:

  This work reports on a drug repurposing effort to target the non-structural protein 1 (Nsp1) of SARS-Cov-2, involved in suppressing host immune function. The authors use a combination of computational, in vitro and cellular assays to this end. They start by virtual screening of an FDA approved drug library, followed by biophysical assays to measure the binding affinity of the top hits as well as molecular dynamics simulations and free energy calculations to confirm binding poses. Finally, in vitro and cellular assays were used to quantify translation inhibition and rescue as well as the production of infectious virus particles. One of the FDA approved drugs, Montelukast, emerges as a promising antiviral drug candidate.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife, ScreenIT

Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike

1. Marco A Díaz-Salinas
2. Qi Li
3. Monir Ejemel
4. Leonid Yurkovetskiy
5. Jeremy Luban
6. Kuang Shen
7. Yang Wang
8. James B Munro

• Curated by eLife

  Evaluation Summary:

  This manuscript describes timely work on the structural dynamics of the SARS-CoV-2 spike protein that will be of importance to a broad range of scientists with interests in the biology of SARS-CoV-2 and COVID-19 and the function of anti-COVID-19 vaccines and antibodies as well as to molecular biophysicists generally interested in single-molecule imaging, protein dynamics, allostery, and molecular mechanisms. The experiments were very well-designed, controlled, and executed, and the data are of very high quality. Nonetheless, although the conclusions seem to be generally supported by the data and consistent with expectations based on previous findings, there are some concerns regarding the modeling and error analysis of some of the data.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Reviewed by eLife, ScreenIT

Ensemble cryo-electron microscopy reveals conformational states of the nsp13 helicase in the SARS-CoV-2 helicase replication-transcription complex

1. James Chen
2. Qi Wang
3. Brandon Malone
4. Eliza Llewellyn
5. Yakov Pechersky
6. Kashyap Maruthi
7. Ed T. Eng
8. Jason K. Perry
9. Elizabeth A. Campbell
10. David E. Shaw
11. Seth A. Darst

Reviewed by ScreenIT