Protein docking along smooth association pathways

We propose a docking method that mimics the way proteins bind. The method a ccounts for the dominant driving forces at the different length scales of t he protein binding process, allowing for an efficient selection of a downhi ll path on the evolving receptor-ligand-free energy landscape. Starting fro m encounter complexes with as much as 10 A rms deviation from the native co nformation, the method locally samples the six dimensional space of rigid-b ody receptor-ligand structures subject to a van der Waals constraint. The s ampling is initially biased only by the desolvation and electrostatic compo nents of the free energy, which capture the partial affinity of unbound str uctures that are more than 4 A away from the native state. Below this thres hold, improved discrimination is attained by adding an increasing fraction of the van der Waals energy to the force field. The method, with no free pa rameters, was tested in eight different sets of independently crystallized receptor-ligand structures consistently predicting bound conformations with the lowest free energies and appropriate stability gap around 2 A from the native complex. This multistage approach is consistent with the underlying kinetics and internal structure of the free energy funnel to the bound sta te. Implications for the nature of the protein binding pathways are also di scussed.