Macromolecular Fitting

Fitting is the standard way of interpreting the information contained in electron-microscopy (EM) maps of macromolecular structures by means of the available atomic structural components. We are immersed in the development of new hybrid methods to combine multiresolution structural information in collaborating with several EM labs.

Multiresolution fitting is a complicated jigsaw puzzle in which the low-resolution 3D EM density map of a macromolecule complex acts as a fuzzy frame to guide the assemblage of interlocking atomic-resolution pieces. When complete, this jigsaw puzzle allows to characterize at near-atomic-detail different functional states of the macromolecules in solution, and hence to a better understanding of the inner workings of the central actors in the principal cellular processes. We develop several approaches to try to solve this puzzle. Firstly, we helped to develop Situs, the the facto standard EM modeling package and we still linked with this project. More recently, we developed ADP_EM a ultra fast rigid-body fitting approximation. In essence, this tool performs an automated and very efficient search of the all possible relative rotations and translations to maximize a density correlation function. This correlation is typically calculated between a target experimental EM map and a simulated probe map obtained by lowering the resolution of the atomic structure to be docked. Although, in many cases the rigid-body approximation suffices it is also frequent the presence of conformational changes between the atomic and the low resolution information. In fact, these changes are likely related to interesting functional aspects. For this reason, we recently extend our study to include flexibility in the fitting process. iMODfit is a novel approximation based on normal mode analysis which offers the possibility of perform flexible fitting in a reliable way.