CONSTRUCTING PROTEIN MODELS FOR LIGAND-RECEPTOR BINDING THERMODYNAMICSIMULATIONS - AN APPLICATION TO A SET OF PEPTIDOMETIC RENIN INHIBITORS

Structure-based design is the application of ligand-receptor modeling to predict the activity of a series of molecules that bind to a common receptor for which the molecular geometry is available. Successful st ructure-based design requires an accurate receptor model which can be economically employed in the design calculations. One goal of the work reported here has been to reduce the size of a model structure of a m acromolecular receptor to allow multiple ligand-receptor molecular dyn amic (MD) simulations to be computationally economical yet still provi de meaningful binding thermodynamic data. A scaled-down 10 Angstrom re ceptor model of the enzyme renin, when subjected to an alternate atomi c mass constraint, maintains the structural integrity of the composite parent crystal structure. A second goal of the work has been to devel op schemes to explore and characterize the protonation states of recep tors and ligand-receptor systems. Application of the charge state char acterization schemes to the hydroxyethylene and statine transition sta te inhibitors of renin in the training set suggests a monoprotonation state of the two active-site aspartate residues, where the lone proton resides on the outer carboxylate oxygen of Asp226 is most likely. For the reduced amide transition state inhibitors an active site consisti ng of both aspartates in the totally ionized state, and the ligand car rying a net +1.0 charge, is most stable and consistent with experiment al data.