Beyond the structural picture: key role of conformational changes for biological function and activity

Speaker: Guillaume Stirnemann, CNRS, Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, Paris, France

Host: Pratyush Tiwary

Abstract: The possibility to obtain three-dimensional molecular structures of biomolecules has been a major revolution in biology during the second half of the XXth century, which allowed to understand the atomistic details of biomolecular function. Therefore, the resolution of structures using X-ray crystallography, and later on, other strategies such as NMR or cryo-EM, is of crucial importance (and impact). Very recently, the development of artificial intelligence approaches (fed with the existing structural databases) such as AlphaFold to predict the native states of proteins has been an incredibly useful step forward in the field.   

Atomistic simulations enable to probe the dynamical evolution of and the fluctuations around these structures, but although a significant effort is directed toward more and more detailed descriptions of atomistic interactions, the exploration of the conformational space is often imperfect. There are many examples for which the static structures provided by the experimental approaches (or Alphafold), even when complemented with molecular dynamics simulations, fail to explain other experimental observations regarding the activity or the function of the biomolecule.

In this presentation, I will discuss a selection of our recent work that demonstrates that a thorough characterization of the biomolecule conformations (not revealed in the experimentally-determined structures) using a variety of enhanced sampling strategies is required to understand the temperature-dependence of enzymatic activity [1,2], the catch-bond properties of an adhesin involved in urinary tract infections [3], or the activity of small ribozyme that serves as a model system for the emergence of the first “living” auto-catalytic systems. 

[1] Maffucci, Laage, Sterpone & Stirnemann, Chem. Eur. J. 26, 10045 (2020)
[2] Maffucci, Laage, Stirnemann & Sterpone, Phys. Chem. Chem. Phys. 22, 18361 (2020) 
[3] Languin-Cattöen, Sterpone & Stirnemann, bioRxiv 2022.11.15.516604 (2022)  

Seminars start at 4:00 pm, and refreshments will be served at 3:45 pm. All seminars are held in the Conference Room (1116) of the Institute for Physical Science and Technology (IPST) Building unless otherwise noted.