How may the use of MD and rigid-body docking algorithms overcome
the protein flexibility problem associated with complex formation?

Graham R. Smith (Cancer Research UK London Research Institute),
Michael J. E. Sternberg (Imperial College London),
Paul A. Bates (Cancer Research UK London Research Institute).
 
 

The formation of a protein-protein complex is a key event in an enormous number of cellular biochemical processes. However, to predict a wild-type complex computationally given the structures of the components (the "protein docking problem") is still difficult in cases where there is any more than a very small change in the conformation of the components upon the formation of the complex.  As a first step to addressing this flexible docking problem, we have used Molecular Dynamics (MD) simulations to investigate the extent to which the conformational fluctuations undergone by proteins in solution reflect the conformational changes that they undergo when they form protein-protein complexes ("induced fit"). To do this, we study a set of over thirty proteins that form such complexes and whose 3-dimensional structures are known, both bound in the complex and unbound. We carry out MD simulations of 5 ns duration with Gromacs, starting from the unbound structures, and analyse the resulting conformational fluctuations in comparison with the structures in the complex.

We find that in some cases the conformational fluctuations observed in MD correlate well with the regions of the proteins that move on complex formation, and in some cases take the protein towards its bound conformation.

Preliminary results are presented on how this information may be used to improve protein-protein docking, both for the test set described above and some targets from recent rounds of CAPRI.