João P. G. L. M. Rodrigues

arXiv2025

Towards better structural models from cryo-electron microscopy data with physics-based methods

Cryo-electron microscopy can now routinely deliver atomic resolution structures for a variety of biological systems. The relevance and value of these structures is directly related to their ability to help rationalize experimental observables, which in turn depends on the quality of model built into the density map. Coupling traditional model building tools with physics-based methods, such as docking, simulation, and modern force fields, has been shown to improve the quality of the resulting structures. Here, we survey the landscape of these hybrid approaches, highlighting their usefulness for medium- and low-resolution datasets, as well as for structures of small molecules, and make the argument that the community stands to benefit from their inclusion in model building and refinement workflows.

q-bio.BM↗

arXiv2014

Sequence co-evolution gives 3D contacts and structures of protein complexes

Protein-protein interactions are fundamental to many biological processes. Experimental screens have identified tens of thousands of interactions and structural biology has provided detailed functional insight for select 3D protein complexes. An alternative rich source of information about protein interactions is the evolutionary sequence record. Building on earlier work, we show that analysis of correlated evolutionary sequence changes across proteins identifies residues that are close in space with sufficient accuracy to determine the three-dimensional structure of the protein complexes. We evaluate prediction performance in blinded tests on 76 complexes of known 3D structure, predict protein-protein contacts in 32 complexes of unknown structure, and demonstrate how evolutionary couplings can be used to distinguish between interacting and non-interacting protein pairs in a large complex. With the current growth of sequence databases, we expect that the method can be generalized to genome-wide elucidation of protein-protein interaction networks and used for interaction predictions at residue resolution.

q-bio.BM↗