3DIANA: 3D Domain Interaction Analysis: A Toolbox for Quaternary Structure Modeling

Electron microscopy (EM) is experiencing a revolution with the advent of a new generation of Direct Electron
Detectors, enabling a broad range of large and flexible structures to be resolved well below 1 nm resolution. Although EM techniques
are evolving to the point of directly obtaining structural data at near-atomic resolution, for many molecules the attainable
resolution might not be enough to propose high-resolution structural models. However, accessing information on atomic coordinates
is a necessary step toward a deeper understanding of the molecular mechanisms that allow proteins to perform specific
tasks. For that reason, methods for the integration of EM three-dimensional maps with x-ray and NMR structural data are being
developed, a modeling task that is normally referred to as fitting, resulting in the so called hybrid models. In this work, we present a
novel application—3DIANA—specially targeted to those cases in which the EM map resolution is medium or low and additional
experimental structural information is scarce or even lacking. In this way, 3DIANA statistically evaluates proposed/potential
contacts between protein domains, presents a complete catalog of both structurally resolved and predicted interacting
regions involving these domains and, finally, suggests structural templates to model the interaction between them. The evaluation
of the proposed interactions is computed with DIMERO, a new method that scores physical binding sites based on the topology of
protein interaction networks, which has recently shown the capability to increase by 200% the number of domain-domain interactions
predicted in interactomes as compared to previous approaches. The new application displays the information at a
sequence and structural level and is accessible through a web browser or as a Chimera plugin at http://3diana.cnb.csic.es.