Paper Report for: Zheng_2018_FASEB.J_32_527

https://doi.org/10.1096/fasebj.2018.32.1_supplement.527.12 Cholinesterases, carboxylesterases and lipases are some of prominent catalytically active proteins with specifically similar, globular tertiary structure fold termed alpha/beta hydrolase fold. Ligand binding, both reversible and covalent, frequently results in small, yet systematic and potentially functionally important changes in the conformation of their alpha carbon backbones that can be easily overseen by commonly used overlays based on overall minimization of backbone atom RMSD analysis. In particular, backbone conformations of cholinesterases - acetylcholinesterase and butyrylcholinesterase - show only small conformational changes. This is revealed in more than 200 PDB deposited cholinesterase X-ray structures in complexes with structurally diverse ligands that affect their function. We developed a novel, reference point based principle for overlay-independent pairwise comparison of liganded and non-liganded alpha carbon backbone conformations from respective PDB (Protein Data Bank) deposited 3D structure entries and encoded it in JAVA based computer algorithm for quick analysis. Comparisons are based on differences in distances between each alpha carbon and chosen reference point in each pair of compared structures, as well as on differences in the angle between center of mass, reference point and each of alpha carbons in the comparison. Combination of the two comparison criteria reveals subset of backbone alpha carbons in two structures that maintains best their relative positions in the 3D space and that can be used as tethering points for overlay of compared structures. Created overlay has capacity to reveal small but systematic local changes in the backbone conformation frequently masked by the overall RMSD minimization approach. Our systematic analysis of a number of PDB deposited alpha/beta hydrolase fold structures revealed small, yet functionally important conformational changes in their backbone consistent with experimental observations and instrumental in revealing molecular mechanisms in respective catalytic reactions. These findings are important for complete molecular target template characterization in the structure based development of novel antidotes of exposure to organophosphates which covalently inhibit this family of enzymes.