Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry.

Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process.

Application of docking methodologies to modeled proteins.

Protein docking is essential for structural characterization of protein interactions. Besides providing the structure of protein complexes, modeling of proteins and their complexes is important for understanding the fundamental principles and specific aspects of protein interactions. The accuracy of protein modeling, in general, is still less than that of the experimental approaches.

Computational Feasibility of an Exhaustive Search of Side-Chain Conformations in Protein-Protein Docking.

Protein-protein docking procedures typically perform the global scan of the proteins relative positions, followed by the local refinement of the putative matches. Because of the size of the search space, the global scan is usually implemented as rigid-body search, using computationally inexpensive intermolecular energy approximations. An adequate refinement has to take into account structural flexibility.

Modeling CAPRI targets 110-120 by template-based and free docking using contact potential and combined scoring function.

The paper presents analysis of our template-based and free docking predictions in the joint CASP12/CAPRI37 round. A new scoring function for template-based docking was developed, benchmarked on the Dockground resource, and applied to the targets. The results showed that the function successfully discriminates the incorrect docking predictions.

Dockground: A comprehensive data resource for modeling of protein complexes.

Characterization of life processes at the molecular level requires structural details of protein interactions. The number of experimentally determined structures of protein-protein complexes accounts only for a fraction of known protein interactions. This gap in structural description of the interactome has to be bridged by modeling.