Molecular recognition. I. Automatic identification of topographic surface features

The phenomenon of molecular recognition depends strongly on surface complementarity between associating molecular units, analogous to the assembly of a three‐dimensional jigsaw puzzle. The driving force for association is solvent entropy, which increases when protrusions of the irregular surface of one subunit fit snugly into invaginations of the other, squeezing out intervening water. To model this process, an algorithm is presented that automatically finds the prominent topographic surface features of rigid α‐helices in proteins of known structure. When the algorithm was applied to two interacting helices from flavodoxin, only a small number of such features were found, and they accounted for the observed complementarity. Using this algorithm, molecular docking can be reduced to a tractable problem by a docking strategy based on exhaustive trial of combinations of surface features.