Biophysical Society Thematic Meeting | Trieste 2024

Emerging Theoretical Approaches to Complement Single-Particle Cryo-EM

Friday Speaker Abstracts

MODELING CONFORMATIONAL TRANSITION OF PROTEINS BY COMBINING CRYO-EM, ALPHAFOLD AND MOLECULAR SIMULATIONS Erik R. Lindahl ; 1 Stockholm University, Biochemistry and Biophysics, Stockholm, Sweden 2 KTH Royal Institute of Technology, Applied Physics, Stockholm, Sweden Single-particle cryo-electron microscopy has potential to provide a much richer view of molecular structure than traditional methods, in particular since the method is often capable of reconstructing multiple states from the same sample. However, it is still common that we cannot identify some states, and that minority classes corresponding to intermediates drown in noise. Even for cases where we are able to model molecular flexibility in terms of continuum descriptions of density, it is considerably more challenging to achieve true time resolution e.g. of kinetics. I will discuss our approaches to combine cryo-EM with simulation-based Markov State Models to resolve complex conformational transitions of ligand-gated ion channels in particular, new methods to efficiently refine molecular structure into cryo-EM density in simulations without requiring constraints on secondary structure, and how we are using generative methods such as AlphaFold to improve the efficiency of these approaches and predict how e.g. ligand binding or pH changes selectively stabilize specific states.

30