Computational analysis of the binding of P1 variants of domain 3 of Turkeyovomucoid inhibitor to Streptomyces griseus protease B

Binding constants for complexes of variants of the ovomucoid inhibitor doma in 3 from turkey (OMTKY3) and Streptomyces griseus protease B (SGPB) have b een computed. On the basis of the crystallographically determined structure s of the complexes, continuum electrostatic calculations have been carried out to evaluate the electrostatic contribution to the binding energy. The h ydrophobic component was computed based on the change in the solvent access ible surface area on complex formation. These two terms were combined linea rly and the parameters for the protein dielectric, atomic solvation paramet er and a constant term were derived using a multivariate fit to the observe d binding energies. The resulting fit shows a high correlation with a multi ple coefficient of determination of 0.79. This indicates that 79% of the va riation in the observed binding energies is explained by the electrostatic and hydrophobic terms. The analysis results in a protein dielectric of 8.2 and an atomic solvation parameter of 30 cal/mol Angstrom(2). As a test, the se parameters were used to calculate the binding energies of complexes of c hymotrypsin and of leukocyte elastase OMTKY3, as well as three other varian ts of OMTKY3 bound to SGPB. As these structures were not used for the multi variate fit, they serve as an independent check on the derived parameters. The calculated energies for the three new variants of OMTKY3 are in good ag reement with the observed values. However, the binding energies of the othe r complexes are poorly predicted. This implies that the parameters that wer e obtained are not transferable. The possible causes for this lack of trans ferability are discussed. (C) 1998 Academic Press.