Assessing the reconstruction of macromolecular assemblies with toleranced models

Abstract

We introduce toleranced models (TOMs), a generic and versatile framework meant to handle models of macromolecular assemblies featuring uncertainties on the shapes and the positions of proteins. A TOM being a continuum of nested shapes, the inner (resp. outer) ones representing high (low) confidence regions, we present topological and geometric statistics assessing features of this continuum at multiple scales. While the topological statistics qualify contacts between instances of protein types and complexes involving prescribed protein types, the geometric statistics scale the geometric accuracy of these complexes. We validate the TOM framework on recent average models of the entire nuclear pore complex (NPC) obtained from reconstruction by data integration, and confront our quantitative analysis against experimental findings related to complexes of the NPC, namely the Y-complex, the T-complex, and the Nsp1-Nup82-Nup159 complex. In the three cases, our analysis bridges the gap between global qualitative models of the entire NPC, and atomic resolution models or putative models of the aforementioned complexes. In a broader perspective, the quantitative assessments provided by the TOM framework should prove instrumental to implement a virtuous loop "model reconstruction-model selection", in the context of reconstruction by data integration.

Probing a continuum of macro-molecular assembly models with graph templates of complexes

“…Our TOM of the NPC being based on the average model from, which involves 16 copies of the Y ‐complex, we could not carry out any evaluation of the fence‐like model. However, our analysis of the Y ‐complex based on the Hasse diagram was globally consistent with an organization in two rings (first model) . Here again, one should be aware of the fact that the TOM being derived from the model proposed by, it relies on the initial datasets used to generate this averaged model.…”

“…The quantitative exploitation of such maps, and the analysis of their coherence with respect to various experimental data motivated the development of toleranced models (TOM), whose main features are recalled now.…”

“…We previously used TOM models to perform three types of analysis . First, the geometric accuracy of contacts was assessed: the larger the value of λ at which a complex appears, the weaker the accuracy of the contacts between its constituting instances.…”

Low-resolution structural modeling of protein interactome

“…The data showed that docking of even highly inaccurate protein models (~6 Å RMSD from the X-ray structure) still yields structurally meaningful results, accurate enough to predict binding interfaces and to serve as starting points for further structural analysis. The utility of the modeled proteins in protein–protein docking was further demonstrated by other systematic studies, involving docking approaches based on computational geometry [31,32] validated on benchmark protein–protein sets [31] and the nuclear pore complex [32], and Rosetta-based docking of antibody–antigen homology models [33]. The template-based docking approaches increasingly focus on the modeled structures as part of the docking protocol [34,35•] or the subject of structural alignment [36••,37••].…”

Unveiling Contacts within Macromolecular Assemblies by Solving Minimum Weight Connectivity Inference (MWC) Problems*

“…In the context of RDI, the models stemming from such analysis do not, in general, achieve atomic resolution. They can, however, be used to bridge the gap to atomic level models of subsystems of the assembly under scrutiny (9,10).…”