Electrostatic lock-and-key model for the analysis of inhibitor recognition by dihydrofolate reductase

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Abstract
We propose a simple electrostatic model for the analysis of ligand binding to proteins. Besides a geometric fit electrostatic complementarity is also needed to allow favourable hydrogen bonding and ion-pair interactions. Nonpolar regions of the ligand and the biomacromolecule active site should match to reduce unfavourable hydrophobic effects, i.e., to lower the Gibbs free energy of the complex in aqueous solution. These principles are applied to the inhibition of dihydrofolate reductase by methotrexate. The enzyme active site is represented by an electrostatic lock which is derived from the macromolecular electrostatic potential and field at certain reference points. The key, defined similarly for the ligand, should fit into the lock to ensure complementarity, i.e., recognition. Hydrogen bonding and ion-pair interactions can be studied by the "potential key" while the "field key" accounts for hydrophobic complementarity. Analyzing the dihydrofolate reductase–methotrexate interaction in the light of the above principles the relative importance of various molecular fragments in binding can be determined.