Structural biology seeks to understand the function of macromolecules by determining the precise position of their atoms. Its traditional methods (X-ray crystallography, NMR, electron microscopy), although effective, offer a static view of macromolecules, limiting the study of their dynamics. A new paradigm is emerging: integrative structural biology, combining several techniques to capture, among other things, molecular dynamics. However, despite improvements in femtosecond serial crystallography, molecular dynamics simulations, and cryo-electron tomography, current methods struggle to reach the functional time scale (milliseconds to seconds).
The advent of new scanning probe microscopy, and in particular the recent development of high-speed atomic force microscopy (HS-AFM), allows molecular movements to be observed on the millisecond scale, but lacks the atomic resolution to revolutionize structural biology. The objective of the proposed topic is to further exploit the use of HS-AFM by modeling detailed atomic structures at the heart of the images obtained. The tasks will be both biophysical and computational, involving the improvement of the existing AFM-Assembly tool, which allows direct spatial adjustment of the atomic coordinates of the target molecule under AFM topography. The aim is to apply this protocol to a new type of big data, namely topographical movies obtained by high-speed AFM.
The thesis will be conducted at the Institute of Structural Biology in Grenoble, within the Methods and Electron Microscopy (MEM) group of the Grenoble Interdisciplinary Research Institute (IRIG). It will be carried out in collaboration with the DyNaMo laboratory in Marseille, which specializes in high-speed AFM data acquisition, as part of a joint ANR funding application.
The scientific interest of the project is major for modern integrative structural biology. The great scientific challenge of the coming years in structural biology is the study and analysis of molecular dynamics, in order to move beyond the current paradigm (instantaneous photography) and participate in the emergence of a new paradigm (real-time movie).