Binding MOAD (Mother of All Databases).

Protein-ligand Binding;Database;Natural Language Processing;Ligand Efficiency;Docking;Biological Chemistry;Science;Bioinformatics

Benson, MarkSaper, Mark A. ;

University of Michigan

关键词: Protein-ligand Binding;    Database;    Natural Language Processing;    Ligand Efficiency;    Docking;    Biological Chemistry;    Science;    Bioinformatics;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/62331/mbensonz_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Binding MOAD (Mother of All Databases) is the largest collection of high-quality,protein-ligand complexes available from the Protein Data Bank. Mining Binding MOADhas 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 highandlow-affinity ligands of nonenzymes are the same size. Furthermore, nonenzymes were foundto have higher ligand efficiencies. The different efficiencies are not due to differences inthe physicochemical properties of the ligands; instead, the amino-acid composition of thepockets are very different despite very similar distributions of amino acids in the overallprotein sequences.This study aims to address the issue of protein flexibility upon ligand binding. Theinfluence of ligand binding on protein flexibility is examined by analyzing a large numberof proteins crystallized with and without ligands. It is shown that, in general, ligand bindingstabilizes 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 inhabitedby apo structures, because the difference between apo and holo structures is smaller thanvariation seen among apo structures themselves. The size of the bound ligand does notappear to matter in determining the rigidification. While ligand binding generally doesnot induce large changes in the backbone, they are significant. Ligand binding does havedistinct impact on the active site, as revealed by all-atom, active-site RMSD and the rangeof c1 variation. Greater variation has been found between these two groups asopposed to within either group by themselves. This suggests that ligand binding inducesactive-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.