Binding MOAD (Mother of All Databases).

Abstract

Binding MOAD (Mother of All Databases) is the largest collection of high-quality, protein-ligand complexes available from the Protein Data Bank. Mining Binding MOAD has revealed physical differences in how enzymes and nonenzymes bind small molecules. High-affinity ligands of enzymes are much larger than those with low affinity, but highand low-affinity ligands of nonenzymes are the same size. Furthermore, nonenzymes were found to have higher ligand efficiencies. The different efficiencies are not due to differences in the physicochemical properties of the ligands; instead, the amino-acid composition of the pockets are very different despite very similar distributions of amino acids in the overall protein sequences. This study aims to address the issue of protein flexibility upon ligand binding. The influence of ligand binding on protein flexibility is examined by analyzing a large number of proteins crystallized with and without ligands. It is shown that, in general, ligand binding stabilizes the protein and results in a smaller backbone root mean square deviation (RMSD) among holo-protein structures, compared the backbone RMSD of the apo-protein structures. Furthermore, the holo structures appear to sample a smaller subset of the space inhabited by apo structures, because the difference between apo and holo structures is smaller than variation seen among apo structures themselves. The size of the bound ligand does not appear to matter in determining the rigidification. While ligand binding generally does not induce large changes in the backbone, they are significant. Ligand binding does have distinct impact on the active site, as revealed by all-atom, active-site RMSD and the range of c1 variation. Greater variation has been found between these two groups as opposed to within either group by themselves. This suggests that ligand binding induces active-site side chains to occupy a different conformational space before and after binding. The influence on the active site could not be easily attributed to features such as ligand size, resolution, protein function, or catalytic composition.