SPECIFICITY OF LIGAND-BINDING IN A BURIED NONPOLAR CAVITY OF T4 LYSOZYME - LINKAGE OF DYNAMICS AND STRUCTURAL PLASTICITY

TO better understand the role of shape complementarity in ligand bindi ng and protein core interactions, the structures have been determined of a set of ligands bound within a cavity-containing mutant of T4 lyso zyme, The interior cavity is seen to consist of two parts that respond very differently to the binding of ligands, First, there is a relativ ely rigid region that does not relax significantly upon binding any li gand, Second, there is a more flexible region that moves to various ex tents in response to binding the different ligands. The part of the bi nding site that remains rigid is characterized by low temperature fact ors and strong protection from hydrogen exchange. This part of the sit e appears to be primarily responsible for discriminating between ligan ds of different shape (i.e., for determining specificity). The more fl exible region, characterized by relatively high temperature factors an d weak protection from hydrogen exchange, allows some promiscuity in b inding by undergoing variable amounts of deformation at essentially th e same energetic cost, This linkage between the dynamic information re presented by crystallographic temperature factors and hydrogen-exchang e behavior on the one hand. and structural plasticity in response to l igand binding on the other hand, suggests a way to improve our underst anding of steric interactions in protein cores and protein-ligand bind ing sites, Ligand design and packing algorithms might take advantage o f this information, requiring complementary interactions where the pro tein is rigid and allowing some overlap in regions where the protein i s flexible.