Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.

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 and -propyl derivatives are virtually identical as are those for the -butyl and -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 having -propyl, -butyl, and -pentyl groups. However, eliminating this unfavorable interaction by introducing a double bond into the side chain of the -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 Δ°, but these are usually offset by corresponding unfavorable changes in -TΔ°; there is little correlation of Δ with changes in the amount of buried nonpolar surface.