Analysis of molecular recognition: Steric electrostatic and hydrophobic complementarity

AbstractWe discuss three important aspects of molecular recognition: steric, electrostatic and hydrophobic. Steric fit means that interacting atoms may not approach each other beyond their van der Waals radii and, simultaneously, crevices should be filled as densely as possible. Electrostatic fit requires the maximum ionic and polar (hydrogen bond or other) interaction between host and guest atoms while the hydrophobic fit corresponds to the association trend between apolar groups in an aqueous medium. Space‐filling models, obtained by molecular graphics, illustrate steric complementarity while we use molecular electrostatic potentials (MEPs) and fields (MEFs) to investigate electrostatic and hydrophobic matching. Molecular regions with negative and positive MEPs attract and repel a positive probe charge, respectively, so we consider them as attracting each other. Furthermore we postulate that regions with MEFs of similar magnitude tend to associate more strongly than those with very different fields (similis simili gaudet principle). We apply the above rules to the study of complementarity in the tryspin‐BPTI complex and in a crystalline association between styrene epoxide as guest and a comphor‐based anthracene derivative as host. We discuss molecular similarity on the same footing as complementarity and give some examples on the application of the concept of the rationalization of relative strengths of trypsin inhibitors.