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Section: New Results

Modeling Macro-molecular Assemblies

Assessing the Reconstruction of Macro-molecular Assemblies with Toleranced Models

Participants : Frédéric Cazals, Tom Dreyfus.

In collaboration with Valérie Doye, Institut Jacques Monod, Paris.

In [20] , we introduce TOleranced Models (TOM), a generic and versatile framework meant to handle models of macro-molecular 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 statistics to assess features of this continuum at multiple scales. While selected statistics target topological aspects (pairwise contacts, complexes involving proteins of prescribed types), others are of geometric nature (geometric accuracy of complexes). We validate the TOM framework on recent average models of the Nuclear Pore Complex (NPC) obtained from reconstruction by data integration, and confront our statistics against experimental findings related to sub-complexes of the NPC. In a broader perspective, the TOM framework should prove instrumental to handle uncertainties of various kind, in particular in electron-microscopy and crystallography.

Probing a Continuum of Macro-molecular Assembly Models with Graph Templates of Sub-complexes

Participants : Frédéric Cazals, Tom Dreyfus.

Reconstruction by data integration is an emerging trend to reconstruct large protein assemblies, but uncertainties on the input data yield average models whose quantitative interpretation is challenging. This paper presents methods to probe fuzzy models of large assemblies against atomic resolution models of sub-systems.

Consider a Toleranced Model (TOM) of a macro-molecular assembly, namely a continuum of nested shapes representing the assembly at multiple scales. Also consider a template namely an atomic resolution 3D model of a sub-system of this assembly—also called a complex. We present algorithms performing a multi-scale assessment of the complexes of the TOM, by comparing the pairwise contacts which appear in the TOM against those of the template. These operations reduce to the comparison of graphs, which we perform by computing Maximal Common Induced Sub-graphs (MCIS) and Maximal Common Edge Sub-graphs (MCES).

We apply this machinery to recent average models of the NPC. First, we show how our contact analysis allows assessing the quality of probability density maps. Regarding particular sub-systems of the NPC, we focus on the Y-complex and on the T-complex. In particular for the latter, our analysis suggests a new 3D template of pairwise contacts.

We believe that these tools should become standard to assess the reconstruction of fuzzy assemblies.

The software associated to these developments is presented in section 5.1.2 .