CORCEMA evaluation of the potential role of intermolecular transferred NOESY in the characterization of ligand-receptor complexes.
We report a theoretical characterization of the intermolecular transferred NOESY (inter-TrNOESY) between ligands and receptor macromolecules that bind reversibly, using a COmplete Relaxation and Conformational Exchange MAtrix (CORCEMA) theory developed in our laboratory. We examine the dependence of inter-TrNOESY on the dissociation constant, off-rate, ligand-to-receptor ratio, and distance variations between protons of interacting species within the complex. These factors are analyzed from simulations on two model systems: (i) neuraminidase complexed to a transition-state analogue; and (ii) thermolysin complexed to a leucine-based inhibitor. The latter case utilizes a three-state model of interaction to simulate the effect of hinge-bending motions on the inter-TrNOESY. Our calculations suggest a potential role for inter-TrNOESY (when observable) and CORCEMA analysis in properly docking the ligand within the active site, and in refining the conformation of the ligand-receptor (active-site) complex. These findings have implications on the structure-based design of ligands (e.g., inhibitors) reversibly binding to receptors (e.g., enzymes).
Curto
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Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham 35294-2041, USA.
Moseley
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Krishna
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D001665:Binding Sites; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D008024:Ligands; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008956:Models, Chemical; D015394:Molecular Structure; D009439:Neuraminidase / Q000737:chemistry; D011522:Protons; D011956:Receptors, Cell Surface / Q000737:chemistry*; D012984:Software; D013820:Thermolysin / Q000037:antagonists & inhibitors / Q000737:chemistry
D008024:Ligands; D046911:Macromolecular Substances; D011522:Protons; D011956:Receptors, Cell Surface; D009439:Neuraminidase; D013820:Thermolysin