Les Houches-TSRC Workshop on Protein Dynamics

Online workshop on May 18+19, 2021.

In-person meeting in Spring/Summer 2022 in the French Alps


Presentation

This workshop is a forum for presenting, teaching and discussing results from the application of state-of-the-art experimental (including, but not limited to, optical spectroscopy, NMR spectroscopy, X-ray crystallography, XFELs, electron microscopy, AFM and scattering methods), and theoretical and computational approaches to studying protein dynamics.

The Les Houches – TSRC Protein Dynamics Workshop complements the long-standing TSRC Protein Dynamics Workshop, held every other year in the odd calendar years at the Telluride Science Research Center in Telluride, Colorado.

The workshop, originally planned in May 2020, was postponed to spring/summer 2022 and an online-version, to be held on May 18+19, 2021.

Online Workshop on May 18+19, 2021

Due to the special situation in 2020 and 2021, we have decided to bring the community together to exchange ideas and keep the spirit active. Thus, we are proud to have a great set of speakers for the 2021 online workshop.

Speakers: (click on title to see abstracts)

James Fraser: "Targeting COVID-19 Viral Enzymes in an Evolving Landscape of Publishing and Peer Review"

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. We conducted a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Neutron diffraction data is guiding hydrogen placement to improve docking calculations. Several hits have promising activity in solution and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors. The role of entropy in modulating binding affinity will also be discussed.

Frank Noe

to be announced soon

Dorothee Kern: "Time travel to the past and future – evolution of energy landscapes for enzymes catalysis"

The essential role of protein dynamics for enzyme catalysis has become more generally accepted. Since evolution is driven by organismal fitness hence the function of proteins, we are asking the question of how enzymatic efficiency has evolved. I will describe how combining the advantages of each technique, NMR, x-ray crystallography inclusion ensemble refinement, MD simulations and Ancestral Sequence Reconstruction (ASR) lead to a thorough description of the energy landscape dictating function.

First, I will address the evolution of enzyme catalysis in response to one of the most fundamental evolutionary drivers, temperature. Using ASR, we answer the question of how enzymes coped with an inherent drop in catalytic speed caused as the earth cooled down over 3.5 billion years. Tracing the evolution of enzyme activity and stability from the hot-start towards modern hyperthermophilic, mesophilic and psychrophilic organisms illustrates active pressure versus passive drift in evolution on a molecular level. Second, I will share a novel approach to visualize the structures of transition-state ensembles (TSEs), that has been stymied due to their fleeting nature despite their crucial role in dictating the speed of biological processes. We determined the transition-state ensemble in the enzyme adenylate kinase by a synergistic approach between experimental high-pressure NMR relaxation during catalysis and molecular dynamics simulations. Third, in “forward evolution” experiments, we discovered how directed evolution reshapes energy landscapes in enzymes to boost catalysis by nine orders of magnitude relative to the best computationally designed biocatalysts. The underlying molecular mechanisms for directed evolution, despite its success, had been illusive, and the general principles discovered here (dynamic properties) open the door for large improvements in rational enzyme design. Finally, visions (and success) for putting protein dynamics at the heart of drug design are discussed.

Claus Seidel: "Integrative dynamic structural biology of proteins with multi-modal fluorescence spectroscopy "

FRET spectroscopy and imaging can provide state-specific information on the structure and dynamics of complex dynamic biomolecular assemblies under ambient conditions with nanosecond time resolution and single-molecule sensitivity. To overcome the sparsity of FRET experiments, we developed procedures to combine these with computer simulations to map biomolecular dynamics and to resolve quantitative integrative structure models at a precision and accuracy better than 3 Å. The integrative structure models are deposited in the new protein data bank, PDB-dev [1-3]. Moreover, we combined super-resolution microscopy via stimulated emission depletion (STED) and Multi-parameter Fluorescence Image Spectroscopy (MFIS) [4] to reach molecular resolution with sub-nanometer precision in molecular imaging of biomolecules and their complexes. While STED-MFIS captures the spatial and temporal information of the cellular context with a resolution below 10 nm, the concurrent measurement of Förster resonance energy transfer (FRET) between an excited donor and acceptor provides a zoom with Ångström precision. Thus, integrative super-resolution FRET image spectroscopy exploits these synergies to reach molecular resolution.

I will introduce the concepts of our novel optical tools and demonstrate recent applications: (1) Detection of a so far hidden functionally important conformational state in the enzyme T4 Lysozyme [5], (2) Resolving the conformational transitions of Guanylate binding proteins (GBPs) during GTP-controlled phase transition to exert their function as part of the innate immune system of mammalian cells [6]. (3) Mapping the dynamic exchange network in chromatin fibers by studying a 12-mer nucleosome array [7].


[1] Kalinin et al.; Nat. Methods 9, 1218-1225 (2012).

[2] Dimura et al.; Curr. Opin. Struct. Biol. 40, 163–185 (2016).

[3] Dimura et. al. Nat Commun. 11, e5394 (2020).

[4] Weidtkamp-Peters et al.; Photochem. Photobiol. Sci. 8, 470-480 (2009).

[5] Sanabria et. al. Nat Commun. 11, e1231 (2020).

[6] Kravets et. al.; eLife 5, e11479 (2016).

[7] Kilic et al.; Nat. Commun. 9, 235 (2018).

Benoît Roux

to be announced soon

Information about our speakers:


"Poster-session" during online workshop.

We think that excellent science is stimulated by exchange - even in times of travel restrictions. Therefore, we plan to have a virtual poster session in virtual breakout rooms, and hopefully the same stimulating setting as the one we usually have. Except for the view on the mountains and the beer. The latter will be back in the 2022 version only (and we are looking forward to it!).

Registration (free of charge)

Please click here to register for the online workshop and for abstract submission.

Registration is free of charge but the places are limited.

The webinar is kindly supported by IST Austria ist.ac.at

The Les Houches/TSRC Protein Dynamics workshop as an in-person meeting will be back in 2022. Click here for more information.

Organizing committee

Enrica Bordignon (Ruhr University Bochum, Germany)

Matthias Heyden (Arizona State University, USA)

Paul Schanda (IBS, Grenoble, France / Institute of Science and Technology Austria)

Ben Schuler (University of Zurich, Switzerland)

Martin Weik (Institut de Biologie Structurale, Grenoble, France)

Sponsors


The Ecole de Physique des Houches is supported by: