Making the invisible protein life visible using integrative biophysical approaches: Structural and dynamic characterization of hidden protein states and allosteric regulatory landscapes
CECAM-Lugano, Lugano, Switzerland
Allosteric regulation is a fundamental mechanism employed by cells to control critical processes such as signal transduction, catalysis, and gene regulation [1-3]. While studies of allosteric regulation have often focused on thermodynamic aspects, there has been an increasing realization of the role of conformational dynamics [4-5]. Recent advances in NMR , cryo electron microscopy [7-8] and biophysical techniques that enabled detailed investigations of large protein systems at atomic resolution have fueled the resurgence of computational and theoretical studies of allosteric regulation, leading to new conceptual outlooks of this long-standing biological phenomenon . High-pressure NMR experiments can be used to detect of low-lying excited functional states, providing another tool to investigate the dynamic energy landscapes . Simulation-based computational approaches allow substantive comparative studies of allosteric networks of regulation and are increasingly being combined with NMR and cryo-EM investigations [11-12]. The ability to measure accurate distances and kinetics with Single-molecule FRET (smFRET) has led to its emergence as an important tool for mapping biomolecular heterogeneities and for measuring structural dynamics over a wide range of timescales [13-15]. Despite the established view that complex protein systems and regulatory complexes often function as dynamic and versatile allosteric machines, the characterization of hidden and rare protein functional states, allosteric conformational transformations and allosteric pathways is still surprisingly limited, calling for the integration of novel structural, biophysical and computational approaches to address these challenges.
The overarching idea of this meeting is to build on the great success and overwhelming positive feedback of our previous CECAM Workshop on “Multiscale simulations of allosteric regulatory mechanisms…” (2018) and CECAM Workshop “Quantifying Protein Dynamics and Allosteric regulation in the cell with emerging technologies: From Cryo-EM and NMR to Networks and Machine Learning” ( 2021).
Our symposium will assemble top researchers in computational structural biology, drug design, crystallography, NMR, cryo-EM, single molecule spectroscopy together with computational biologists, theoreticians, computer scientists and machine learning experts. Among confirmed speakers are members of the USA National Academy of Sciences and Royal Society. The meeting will feature many prominent computational biologists and top crystallographers, NMR experts and leaders in cryo-EM technology and FRET approaches as well as leaders in AI and Machine Learning.
We bring together an exciting group of experts in diverse areas : from computational and structural biology, theory and simulations to biophysics, to artificial intelligence, machine learning and drug discovery.
The format of our meeting will include not only lectures and oral presentations but also a series of round table discussions, focused group sessions, and poster presentations.
We are planning to cover a number of topics including but not limited to :
a) Theoretical and computational models of allosteric regulation on different time scales: accelerated MD simulations, Markov State models, non-equilibrium simulation methods.
b) Experiment-informed modeling of allosteric biomolecular assemblies, network models, dynamic network flows, NMR-based simulation approaches, systems-biology simulations of regulation in the cellular environment.
b) New methods and developments in the non-equilibrium simulation methods for modeling of allosteric ensembles and pathways
c) Latest developments in structural characterization of allosteric molecular events and hidden functional states important for allosteric function using cryo-EM, NMR, smFRET spectroscopy and integrative computational biophysics approaches.
d) Computer simulation methods and experimental NMR, smFRET tools for unveiling the invisible aspects of protein ‘life’ including the determination of hidden protein states.
e) Integration of smFRET tools with advanced sampling and non-equilibrium simulation methods for studies of slow conformational dynamics and allosteric transformations in protein systems
f) Open questions and challenges in the field, particularly opportunities for integration of NMR, smFRET and advanced computational sampling approaches.
The main objectives of the workshop are:
- Focus on the latest developments in structural characterization of allosteric molecular events and hidden functional states important for allosteric function using cryo-EM, NMR, smFRET spectroscopy and integrative computational biophysics approaches.
- Discuss progress and identify integrative tools for unveiling the invisible aspects of protein ‘life’ including the determination of hidden protein states.
- Analyze and discuss new methods and developments in the non-equilibrium simulation methods for modeling of allosteric ensembles and pathways.
- Focus on approaches for integration of smFRET tools with advanced sampling and non-equilibrium simulation methods for studies of slow conformational dynamics and allosteric transformations in protein systems.
- Develop a perspective on the progress and role of emerging technologies in quantifying dynamics and kinetics of allosteric events and detecting hidden rare functional states (high-pressure NMR, cryo-EM. smFRET, experiment-guided biophysical modeling, AI and machine learning as enabling tools for integration of the theory and experiment).
- Discuss open issues and challenges in the field, particularly opportunities for integration of NMR, smFRET and advanced computational sampling approaches
- Bring together cryo-EM. NMR, smFRET and computational communities to develop strategic views on allosteric phenomena in molecular biology.
- Discuss Open Science, Shared Infrastructure and Data Exchange between cryo-EM, NMR, smFRET and computational communities to develop strategic views on allosteric phenomena in molecular biology.
- Open exchange and discussion about new developments and current status in the field.
- Provide opportunities and engage students and early-career researchers to discuss their projects in a poster session and contributed talks.
- Address gender inequality in science by promoting participation of women and minorities.
- Promote networking between students, early-career and more experienced researchers.
New Focused Topics for Talks and Round-Table Discussions:
- COVID-19 Research : New Era for Structural and Computational Biology
- Advances in Artificial Intelligence and Impact on Structural Biology, Biomedical Sciences and Integrative Biophysical Approaches
- AlphaFold Present and Future : From Structures to Dynamics, Mechanisms and Engineering
- ChatGPT OpenAI : Future of Science, Education and Publishing
Francesco Gervasio (Université de Genève) - Organiser
Gennady Verkhivker (Chapman University School of Pharmacy) - Organiser