What is the relationship between the global structures of apo and holo proteins?

It is well known that ligand binding and release may induce a wide range of structural changes in a receptor protein, varying from small movements of loops or side chains in the binding pocket to large-scale domain hinge-bending and shear motions or even partial unfolding that facilitates the capture and release of a ligand. An interesting question is what in general are the conformational changes triggered by ligand binding? The aim of this work is analyze the magnitude of structural changes in a protein resulting from ligand binding to assess if the state of ligand binding needs to be included in template-based protein structure prediction algorithms. To address this issue, a nonredundant dataset of 521 paired protein structures in the ligand-free and ligand-bound form was created and used to estimate the degree of both local and global structure similarity between the apo and holo forms. In most cases, the proteins undergo relatively small conformational rearrangements of their tertiary structure upon ligand binding/release (most root-mean-square-deviations from native, RMSD, are <1 A). However, a clear difference was observed between single- and multiple-domain proteins. For the latter, RMSD changes greater than 1 A and sometimes larger were found for almost 1/3 of the cases; these are mainly associated with large-scale hinge-bending movements of entire domains. The changes in the mutual orientation of individual domains in multiple-domain proteins upon ligand binding were investigated using a mechanistic model based on mass-weighted principal axes as well as interface buried surface calculations. Some preferences toward the anticipated mechanism of protein domain movements are predictable based on the examination of just the ligand-free structural form. These results have applications to protein structure prediction, particularly in the context of protein domain assembly, if additional information concerning ligand binding is exploited.