title: Entropic contributions and the influence of the hydrophobic environment in promiscuous protein-protein association.
abstract: The mechanisms by which a promiscuous protein can strongly interact with several different proteins using the same binding interface are not completely understood. An example is protein kinase A (PKA), which uses a single face on its docking/dimerization domain to interact with multiple A-kinase anchoring proteins (AKAP) that localize it to different parts of the cell. In the current study, the configurational entropy contributions to the binding between the AKAP protein HT31 with the D/D domain of RII alpha-regulatory subunit of PKA were examined. The results show that the majority of configurational entropy loss for the interaction was due to decreased fluctuations within rotamer states of the side chains. The result is in contrast to the widely held approximation that the decrease in the number of rotamer states available to the side chains forms the major component. Further analysis showed that there was a direct linear relationship between total configurational entropy and the number of favorable, alternative contacts available within hydrophobic environments. The hydrophobic binding pocket of the D/D domain provides alternative contact points for the side chains of AKAP peptides that allow them to adopt different binding conformations. The increase in binding conformations provides an increase in binding entropy and hence binding affinity. We infer that a general strategy for a promiscuous protein is to provide alternative contact points at its interface to increase binding affinity while the plasticity required for binding to multiple partners is retained. Implications are discussed for understanding and treating diseases in which promiscuous protein interactions are used.
authors.affiliation: Departments of Chemistry and Biochemistry and Pharmacology, Center for Theoretical Biological Physics Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093-0365, USA.
authors.forename: Chia-En A
authors.initials: CE
authors.lastname: Chang
authors.forename: William A
authors.initials: WA
authors.lastname: McLaughlin
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baron
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry*; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000737:chemistry*; D019277:Entropy; D057927:Hydrophobic and Hydrophilic Interactions; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation
chemical_list: D054758:A Kinase Anchor Proteins; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D010455:Peptides