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New insights into the mechanism of protein–protein association

Association of a protein complex follows a two‐step mechanism, with the first step being the formation of an encounter complex that evolves into the final complex. Here, we analyze recent experimental data of the association of TEM1‐β‐lactamase with BLIP using theoretical calculations and simulation. We show that the calculated Debye–Hückel energy of interaction for a pair of proteins during association resembles an energy funnel, with the final complex at the minima. All attraction is lost at inter‐protein distances of 20 Å, or rotation angles of >60° from the orientation of the final complex. For faster‐associating protein complexes, the energy funnel deepens and its volume increases. Mutations with the largest impact on association (hotspots for association) have the largest effect on the size and depth of the energy funnel. Analyzing existing evidence, we suggest that the transition state along the association pathway is the formation of the final complex from the encounter complex. Consequently, pairs of proteins forming an encounter complex will tend to dissociate more readily than to evolve into the final complex. Increasing directional diffusion by increasing favorable electrostatic attraction results in a faster forming and slower dissociating encounter complex. The possible applicability of electrostatic calculations for protein–protein docking is discussed. Proteins 2001;45:190–198. © 2001 Wiley‐Liss, Inc.