How common is the funnel-like energy landscape in protein-protein interactions?

The goal of this study is to verify the concept of the funnel-like intermol ecular energy landscape in protein-protein interactions by use of a series of computational experiments. Our preliminary analysis revealed the existen ce of the funnel in many protein-protein interactions. However, because of the uncertainties in the modeling of these interactions and the ambiguity o f the analysis procedures, the detection of the funnels requires detailed q uantitative approaches to the energy landscape analysis. A number of such a pproaches are presented in this study. We show that the funnel detection pr oblem is equivalent to a problem of distinguishing between distributions of low-energy intermolecular matches in the funnel and in the low-frequency l andscape fluctuations. If the fluctuations are random, the decision about w hether the minimum is the funnel is equivalent to determining whether this minimum is significantly different from a would-be random one. A database o f 475 nonredundant cocrystallized protein-protein complexes was used to re- dock the proteins by use of smoothed potentials. To detect the funnel, we d eveloped a set of sophisticated models of random matches. The funnel was co nsidered detected if the binding nl ea was mole populated by the low-energy docking predictions than by the matches generated in the random models. Th e number of funnels detected by use of different random models varied signi ficantly. However, the results confirmed that the funnel may be the general feature in protein-protein association.