title: Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.
abstract: Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and tripeptides of the general form Ac-pTyr-Xaa-Asn in which the Xaa residue bears a linear alkyl chain varying in length from 1-5 carbon atoms. Binding affinity increases upon adding a methylene group to the Ala derivative, but further chain extension gives no extra enhancement in potency. The thermodynamic signatures of the ethyl andn-propyl derivatives are virtually identical as are those for then-butyl andn-pentyl analogs. Crystallographic analysis of the complexes reveals a high degree of similarity in the structure of the domain and the bound ligands with the notable exception that there is a gauche interaction in the side chains in the bound conformations of ligands havingn-propyl,n-butyl, andn-pentyl groups. However, eliminating this unfavorable interaction by introducing aZ-double bond into the side chain of then-propyl analog does not result in an increase in affinity. Increases in the amount of nonpolar surface that is buried upon ligand binding correlate with favorable changes in ΔH°, but these are usually offset by corresponding unfavorable changes in -TΔS°; there is little correlation of ΔCpwith changes in the amount of buried nonpolar surface.
authors.affiliation: Department of Chemistry and Biochemistry, The Institute of Cellular and Molecular Biology, and The Texas Institute of Drug and Diagnostic Development, The University of Texas, Austin, Texas 78712.
authors.forename: James M
authors.initials: JM
authors.lastname: Myslinski
authors.affiliation: Department of Chemistry and Biochemistry, The Institute of Cellular and Molecular Biology, and The Texas Institute of Drug and Diagnostic Development, The University of Texas, Austin, Texas 78712.
authors.forename: John H
authors.initials: JH
authors.lastname: Clements
authors.affiliation: Department of Chemistry and Biochemistry, The Institute of Cellular and Molecular Biology, and The Texas Institute of Drug and Diagnostic Development, The University of Texas, Austin, Texas 78712.
authors.forename: John E
authors.initials: JE
authors.lastname: Delorbe
authors.affiliation: Department of Chemistry and Biochemistry, The Institute of Cellular and Molecular Biology, and The Texas Institute of Drug and Diagnostic Development, The University of Texas, Austin, Texas 78712.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Martin