Prediction and design of macromolecular structures and interactions

Abstract

In this article, I summarize recent work from my group directed towards developing an improved model of intra and intermolecular interactions and applying this improved model to the prediction and design of macromolecular structures and interactions. Prediction and design applications can be of great biological interest in their own right, and also provide very stringent and objective tests which drive the improvement of the model and increases in fundamental understanding. I emphasize the results from the prediction and design tests that suggest progress is being made in high-resolution modelling, and that there is hope for reliably and accurately computing structural biology.

Figure 1

Schematic diagram of Rosetta structure prediction and design efforts.

Figure 2

Comparison of Top7 X-ray crystal structure (red) and design model (blue). (a) Calpha overlay; (b), detail of sidechain packing in the core.

Figure 3

CAPRI protein–protein docking results. (a) (i): Energy spectrum of models generated in global docking calculations carried out before experimental structures were released; (ii) free energy landscape mapped out by starting trajectories at lowest energy points sampled in global docking runs. (b): comparison of predicted (blue) rigid body orientation with X-ray crystal structure (red and yellow). (c): close up of interface showing that in addition to the rigid body orientation also the detailed conformations of the sidechains were correctly predicted. The predicted models are those submitted to the CAPRI organizers and are the lowest energy models found in the global and local searches shown on the (a).