SHAPE COMPLEMENTARITY AT PROTEIN-PROTEIN INTERFACES

A matching algorithm using surface complementarity between receptor an d ligand protein molecules is outlined. The molecular surfaces are rep resented by ''critical points,'' describing holes and knobs. Holes (ma xima of a shape function) are matched with knobs (minima). This simple and appealing surface representation has been previously described by Connolly [(1986) Biopolymers, Vol. 25, pp. 1229-1247]. However, attem pts to implement this description in a docking scheme have been unsucc essful (e.g., Connolly, ibid.). In order to decrease the combinatorial complexity, and to make the execution time affordable, four critical hole/knob point matches were sought. This approach failed since some b ound interfaces are relatively flat and do not possess four critical p oint matches. On the other hand, matchings of fewer critical points re quire a very time-consuming, full conformational (grid) space search [ Wang, (1991) Journal of Computational Chemistry, Vol. 12, pp. 746-750] . Here we show that despite the initial failure of this approach, with a simple and straightforward modification in the matching algorithm, this surface representation works well. Out of the 16 protein-protein complexes we have tried, 15 were successfully docked, including two im munoglobulins. The entire molecular surfaces were considered, with abs olutely no additional information regarding the binding sites. The who le process is completely automated, with no manual intervention, eithe r in the input atomic coordinate data, or in the matching. We have bee n able to reach this level of performance with the hole/knob surface d escription by using pairs of critical points along with their surface normals in the calculation of the transformation matrix. The success o f this approach suggests that future docking methods should use geomet ric docking as the first screening filter. As a geometrically based do cking methodology predicts correct, along with incorrect, receptor-lig and bound conformations, all solutions need to undergo energy screenin g to differentiate between them. (C) 1994 John Wiley & Sons, Inc.