Biophysics

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

Analyzing SARS CoV-2 Patient Data Using Quantum Supervised Machine Learning

1. Zara Yu

Reviewed by ScreenIT

Structural Basis of the Main Proteases of Coronavirus Bound to Drug Candidate PF-07321332

1. Jian Li
2. Cheng Lin
3. Xuelan Zhou
4. Fanglin Zhong
5. Pei Zeng
6. Yang Yang
7. Yuting Zhang
8. Bo Yu
9. Xiaona Fan
10. Peter J. McCormick
11. Rui Fu
12. Yang Fu
13. Haihai Jiang
14. Jin Zhang

Reviewed by ScreenIT

Mg2+-dependent conformational equilibria in CorA and an integrated view on transport regulation

1. Nicolai Tidemand Johansen
2. Marta Bonaccorsi
3. Tone Bengtsen
4. Andreas Haahr Larsen
5. Frederik Grønbæk Tidemand
6. Martin Cramer Pedersen
7. Pie Huda
8. Jens Berndtsson
9. Tamim Darwish
10. Nageshewar Rao Yepuri
11. Anne Martel
12. Thomas Günther Pomorski
13. Andrea Bertarello
14. Mark Sansom
15. Mikaela Rapp
16. Ramon Crehuet
17. Tobias Schubeis
18. Kresten Lindorff-Larsen
19. Guido Pintacuda
20. Lise Arleth

• Curated by eLife

  Evaluation Summary:

  Magnesium is an essential metal that is involved in vital biological processes. Using a model system, the authors discovered the presence of a conformational equilibrium between different unligated states that may explain the mechanism of magnesium transport. The combination of several different approach support the hypothesis that molecular motion is involved in the transport mechanism of Mg2+ ions.

  (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. The reviewers remained anonymous to the authors.)

Reviewed by eLife

The MIDAS domain of AAA mechanoenzyme Mdn1 forms catch bonds with two different substrates

1. Keith J Mickolajczyk
2. Paul Dominic B Olinares
3. Brian T Chait
4. Shixin Liu
5. Tarun M Kapoor

• Curated by eLife

  Evaluation Summary:

  Mickolajczyk et al. report the development of a new optical tweezers-based unbinding-force assay to characterize the interaction between the MIDAS domain of the mechanoenzyme Mdn1 and the ubiquitin-like (UBL) domain-containing ribosomal proteins Rsa1 and Ytm1. The authors show that the bond between MIDAS and Rsa1/Ytm1 can be best explained by a catch-slip bond behavior. The observations suggest that catch bonding between MIDAS and UBL domains plays a key role in the Mdn1-mediated ribosomal biogenesis. The reported results will be of interesting for the ribosomal and single-molecule biophysics communities and the developed DNA-tether-based optical tweezers assay will be useful for characterizing other molecular bonds.

  (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

The molecular mechanism of load adaptation by branched actin networks

1. Tai-De Li
2. Peter Bieling
3. Julian Weichsel
4. R Dyche Mullins
5. Daniel A Fletcher

• Curated by eLife

  Evaluation Summary:

  This in vitro study proposes to explain why branched actin filament networks, similar to the ones encountered in migrating cells, become denser when they grow against a mechanical load. This question is of broad interest, and has long been waiting for a molecular-scale explanation. Building on their previously published tools and results, the authors perform a series of elegant and clever experiments, and convincingly identify key molecular mechanisms. Importantly, the results also confirm the Brownian ratchet model for actin assembly. This study captures several important features of branched filament networks, and should become a reference on the topic.

  (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. The reviewers remained anonymous to the authors.)

Reviewed by eLife

Ligand binding remodels protein side-chain conformational heterogeneity

1. Stephanie A Wankowicz
2. Saulo H de Oliveira
3. Daniel W Hogan
4. Henry van den Bedem
5. James S Fraser

• Curated by eLife

  Evaluation Summary:

  This work attempts to extract information about protein thermodynamics from X-ray crystallography data, which is a challenging problem. This work presents a comprehensive examination of the structural transitions associated with small molecule binding to proteins. The heterogenous pattern of order parameter changes in response to ligand binding implies that the approach is identifying new information. This work offers insights into ligand binding affinity and specificity mechanisms, suggesting that distal (allosteric) perturbations represent a possible avenue to modulate protein function.

  (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. The reviewers remained anonymous to the authors.)

Reviewed by eLife

Lactoferricins impair the cytosolic membrane of Escherichia coli within a few seconds and accumulate inside the cell

1. Enrico F Semeraro
2. Lisa Marx
3. Johannes Mandl
4. Ilse Letofsky-Papst
5. Claudia Mayrhofer
6. Moritz PK Frewein
7. Haden L Scott
8. Sylvain Prévost
9. Helmut Bergler
10. Karl Lohner
11. Georg Pabst

• Curated by eLife

  Evaluation Summary:

  This paper presents groundbreaking data on the effects of antimicrobial peptides on bacterial cells, obtained by time resolved small angle X-ray and neutron scattering experiments coupled to stopped-flow mixing. Application of this approach to cells is highly innovative and provides ms time resolution, and information on multiple length scales (from conformational changes in the cell, to structural changes in the membranes). This is an important extension of the effort of the scientific community to study model membranes. The main result is that the peptides reach the cytosol in a few seconds, accumulating to high concentrations. The data analysis should be improved, and many conclusions are speculative, in particular on the mechanism of entry of the peptides.

  (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