Molecular recognition in biological systems: from activation to inhibition.

Abstract

A fine-tuned system of molecular recognition is a fundamental feature of all biological processes. Although the basic principles of how molecular surfaces fit together in a complementary fashion have been established to a first approximation, the details of the interplay between electrostatic, steric, entropic and solvation effects are not well understood. To provide insight into the stereochemical factors that govern recognition and packing at protein interfaces, a host of biochemical and biophysical techniques have been applied. Perhaps the most widely used of these techniques are mutagenesis and crystallography, and when used together they have proved to be extremely powerful in defining the functional elements that are important in protein interactions. Using these protein-engineering techniques we have focused our studies on the role of molecular recognition in two important, but distinctly different, biological processes: ( 1) the role of molecular recognition in receptor activation, and (2) the stereochemical factors that define specificity and provide binding energy to inhibitors that are associated with their target proteinases. Our findings, discussed below, suggest that the conventional wisdom about specificity and binding needs to be rethought.