OPTIMIZING ELECTROSTATIC AFFINITY IN LIGAND-RECEPTOR BINDING - THEORY, COMPUTATION, AND LIGAND PROPERTIES

The design of a tight-binding molecular ligand involves a tradeoff bet ween an unfavorable electrostatic desolvation penalty incurred when th e ligand binds a receptor in aqueous solution and the generally favora ble intermolecular interactions made in the bound state. Using continu um electrostatic models we have developed a theoretical framework for analyzing this problem and have shown that the Ligand-charge distribut ion can be optimized to produce the most favorable balance of these op posing free energy contributions [L.-P. Lee and B. Tidor, J. Chem.-Phy s. 106, 8681 (1997)]. Herein the theoretical framework is extended and calculations are performed for a wide range of model receptors. We ex amine methods for computing optimal ligands (including cases where the re is conformational change) and the resulting properties of optimized ligands. In particular, indicators are developed to aid in the determ ination of the deficiencies in a specific ligand or basis. A connectio n is established between the optimization problem here and a generaliz ed image problem, from which an inverse-image basis set can be defined ; this basis is shown to perform very well in optimization calculation s. Furthermore, the optimized ligands are shown to have favorable elec trostatic binding free energies (in contrast to many natural ligands), there is a strong correlation between the receptor desolvation penalt y and the optimized binding free energy for fixed geometry, and the li gand and receptor cannot generally be mutually optimal. Additionally, we introduce the display of complementary desolvation and interaction potentials and the deviation of their relationship from ideal as a use ful tool for judging effective complementarity. Scripts for computing and displaying these potentials with GRASP are available at http://mit .edu/tidor. (C) 1998 American Institute of Physics. [S0021-9606(98)505 41-7].