Conformational diversity of ligands bound to proteins.

The phenomenon of molecular recognition, which underpins almost all biological processes, is dynamic, complex and subtle. Establishing an interaction between a pair of molecules involves mutual structural rearrangements guided by a highly convoluted energy landscape, the accurate mapping of which continues to elude us. Increased understanding of the degree to which the conformational space of a ligand is restricted upon binding may have important implications for docking studies, structure refinement and for function prediction methods based on geometrical comparisons of ligands or their binding sites. Here, we present an analysis of the conformational variability exhibited by three of the most ubiquitous biological ligands in nature, ATP, NAD and FAD. First, we demonstrate qualitatively that these ligands bind to proteins in widely varying conformations, including several cases in which parts of the molecule assume energetically unfavourable orientations. Next, by comparing the distribution of bound ligand shapes with the set of all possible molecular conformations, we provide a quantitative assessment of previous observations that ligands tend to unfold when binding to proteins. We show that, while extended forms of ligands are indeed common in ligand-protein structures, instances of ligands in almost maximally compact arrangements can also be found. Thirdly, we compare the conformational variation in two sets of ligand molecules, those bound to homologous proteins, and those bound to unrelated proteins. Although most superfamilies bind ligands in a fairly conserved manner, we find several cases in which significant variation in ligand configuration is observed.