Hydrophobic ligands, protein-ligand binding

We review the subject of noncovalent interactions in proteins with particular emphasis on the so-called weakly polar interactions. First, the physical bases of the noncovalent electrostatic interactions that stabilize protein structure are discussed. Second, the four types of weakly polar interactions that have been shown to occur in proteins are described with reference to some biologically significant examples of protein structure stabilization and protein-ligand binding. Third, hydrophobic effects in proteins are discussed. Fourth, an hypothesis regarding the biological importance of the weakly polar interaction is advanced. Finally, we propose adoption of a systematic classification of electrostatic interactions in proteins. 

Young, T., Abel, R., Kim, B., Berne, B.J., and Friesner, R.A. (2007) Motifs for molecular recognition exploiting hydrophobic enclosure in protein—ligand binding. Proceeding of the National Academy of Sciences of the United States of America, 104, 808-813. 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

FIGURE 1.4 Ligand-binding plots showing hydrogen-bonding interactions and distances and hydrophobic contacts for (a) the sucrose molecule in the A. maxima OCP structure and (b) the 3 -hydroxyechinenone molecule. Residues labeled in bold are absolutely conserved in the primary structure of the OCP. (From Wallace, A.C. et al., Protein Eng., 8, 127, 1995.)... 

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