Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

Boby ML, Fearon D, Ferla M, Filep M, Robinson MC, The COVID Moonshot Consortium, Chodera JD, Lee A, London N, von Delft F.
Science 382:eabo7201, 2023 [DOI] [PDF] [ready to use data]

We report the discovery of a new oral antiviral non-covalent SARS-CoV-2 main protease inhibitor developed by the COVID Moonshot, a global open science collaboration leveraging free energy calculations on Folding@home and ML-accelerated synthesis planning, now in accelerated preclinical studies funded by an $11M grant from the WHO ACT-A program via the Wellcome Trust. We are currently in discussions with generics manufacturers about partnering with us throughout clinical trials to ensure we can scale up production for global equitable and affordable access once approved by regulatory agencies.

Antibodies to the SARS-CoV-2 receptor-binding domain that maximize breadth and resistance to viral escape

Tyler N Starr, Nadine Czudnochowski, Fabrizia Zatta, Young-Jun Park, Zhuoming Liu, Amin Addetia, Dora Pinto, Martina Beltramello, Patrick Hernandez, Allison J Greaney, Roberta Marzi, William G Glass, Ivy Zhang, Adam S Dingens, John E Bowen, Jason A Wojcechowskyj, Anna De Marco, Laura E Rosen, Jiayi Zhou, Martin Montiel-Ruiz, Hannah Kaiser, Heather Tucker, Michael P Housley, Julia Di Iulio, Gloria Lombardo, Maria Agostini, Nicole Sprugasci, Katja Culap, Stefano Jaconi, Marcel Meury, Exequiel Dellota, Elisabetta Cameroni, Tristan I Croll, Jay C Nix, Colin Havenar-Daughton, Amalio Telenti, Florian A Lempp, Matteo Samuele Pizzuto, John D Chodera, Christy M Hebner, Sean PJ Whelan, Herbert W Virgin, David Veesler, Davide Corti, Jesse D Bloom, Gyorgy Snell
Nature, in press. [DOI] [bioRxiv] [GitHub]

We comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor binding domain, including the parent antibody of the recently approved Vir antibody drug (Sotrovimab), illuminating escape mutations with structural and dynamic insight into their mechanism of action.

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

Emma C. Thompson, Laura E. Rosen, James G. Shepherd, Robert Spreafico, Ana da Silva Filipe, Jason A. Wojcechowskyj, Chris Davis, Luca Piccoli, David J. Pascall, Josh Dillen, Spyros Lytras, Nadine Czudnochowski, Rajiv Shah, Marcel Meury, Natasha Jesudason, Anna De Marco, Kathy Li, Jessia Bassi, Aine O’Toole, Dora Pinto, Rachel M. Colqohoun, Katja Culap, Ben Jackson, Fabrizia Zatta, Andrew Rambaut, Stefano Jaconi, Vattipali B. Sreenu, Jay Nix, Ivy Zhang, Ruth F. Jarrett, William G. Glass, Martina Beltramello, Kyriaki Nomikou, Matteo Pizzuto, Lily Tong, Elisabetta Cameroni, Tristan I. Croll, Natasha Johnson, Julia Di Iulio, Arthur Wickenhagen, Alessandro Ceschi, Aoife M. Harbison, Daniel Mair, Paolo Ferrari, Katherine Smollett, Federica Sallusto, Stephen Carmichael, Christian Garzoni, Jenna Nichols, Massimo Galli, Joseph Hughes, Agostino Riva, Antonia Ho, Marco Schiuma, Malcolm G. Semple, Peter J. M. Openshaw, Elisa Fadda, J. Kenneth Baillie, John D. Chodera, The ISARIC4C Investigators, the COVID-19 Genomics UK (COG-UK) consortium, Suzannah J. Rihn, Samantha J. Lycett, Herbert W. Virgin, Amalio Telenti, Davide Corti, David L. Robertson, and Gyorgy Snell.

Cell 184:1171, 2022. [DOI] [PDF] [bioRxiv] [Supplementary Info] [Folding@home data]

New mutations that enhance the affinity of SARS-CoV-2 spike protein for human ACE2—and potentially pose threats to antibody-based therapeutics and vaccines for COVID-19—are already emerging in the wild. We characterize and describe sentinel mutations of SARS-CoV-2 in the wild that herald challenges for combatting COVID-19, and use simulations of the RBD-ACE2 interface on Folding@home to biophysically characterize why these mutations can lead to enhanced affinity.

Ancestral reconstruction reveals mechanisms of ERK regulatory evolution

Dajun Sang, Sudarshan Pinglay, Rafal P Wiewiora, Myvizhi E Selvan, Hua Jane Lou, John D Chodera, Benjamin E Turk, Zeynep H Gümüş, and Liam J Holt.
eLife 2019;8:e38805 [DOI] [eLife] [PDF] [Folding@home data]

To understand how kinase regulation by phosphorylation emerged, we reconstruct the common ancestor of CDKs and MAPKs, using biochemical experiments and massively parallel molecular simulations to study how a few mutations were sufficient to switch ERK-family kinases from high- to low-autophosphorylation.

The dynamic conformational landscapes of the protein methyltransferase SETD8

Rafal P. Wiewiora*, Shi Chen*, Fanwang Meng, Nicolas Babault, Anqi Ma, Wenyu Yu, Kun Qian, Hao Hu, Hua Zou, Junyi Wang, Shijie Fan, Gil Blum, Fabio Pittella-Silva, Kyle A. Beauchamp, Wolfram Tempel, Hualing Jiang, Kaixian Chen, Robert Skene, Y. George Zheng, Peter J. Brown, Jian Jin, John D. Chodera+, and Minkui Luo+.
eLife 8:e45403, 2019. [DOI] [bioRxiv] [GitHub] [OSF] [movies] [MSKCC blog post]
* These authors contributed equally to this work
+ Co-corresponding authors

In this work, we show how targeted X-ray crystallography using covalent inhibitors and depletion of native ligands to reveal structures of low-population hidden conformations can be combined with massively distributed molecular simulation to resolve the functional dynamic landscape of the protein methyltransferase SETD8 in unprecedented atomistic detail. Using an aggregate of six milliseconds of fully atomistic simulation from Folding@home, we use Markov state models to illuminate the conformational dynamics of this important epigenetic protein.

All Folding@home simulation trajectories for this paper are available on the Open Science Framework.

The trajectories generated for this project were used as the source for a unique musical composition 'Metastable' by George Holloway, performed by the Ligeti String Quartet with visual accompaniment from Robert Arbon.

A water-mediated allosteric network governs activation of Aurora kinase A

Cyphers S, Ruff E, Behr JM, Chodera JD, and Levinson NM.
Nature Chemical Biology 13:402, 2017. [DOI] [PDF] [GitHub]

Over 50 microseconds of aggregate simulation data on Folding@home reveal a surprisingly stable hydrogen bond network underlies allosteric activation by Tpx2.

Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Xu Jianing, Pham CG, Albanese SK, Dong Yiyu, Oyama T, Lee CH, Rodrik-Outmezguine V, Yao Z, Han S, Chen D, Parton DL, Chodera JD, Rosen N, Cheng EH, and Hsieh J. Journal of Clinical Investigation 126:3526, 2016. [DOI] [PDF]

In work with the James Hsieh lab at MSKCC, we examine the surprising origin of how different clinically-identified cancer-associated mutations in MTOR activate the kinase through distinct mechanisms.