Journal of Molecular Biology
CommunicationAnatomy of hot spots in protein interfaces1
Section snippets
Hot spots are protected from bulk solvent
Hot spots of binding energy located near the center of the interface are a general property of the interfaces we examined (Figure 2), as was previously shown for human growth hormone bound to its receptor (Clackson & Wells, 1995). The residues that make up each hot spot tend to cluster together near the center of the interface; very few residues that contribute a large amount of binding energy (>3.5 kcal/mol) are at the edge of an interface. There is no purely geometric reason that hot spot
Amino acid preferences in hot spots
The distribution of percentages of different amino acid types that occur in hot spots (contribute more than 2 kcal/mol to a binding interaction) in our database is strikingly non-random (Table 2). Only three amino acids appear in hot spots with a frequency of more than 10%; 21% of tryptophan, 13.3% of arginine and 12.3% of tyrosine residues are in hot spots. However, many amino acids are found in hot spots very rarely. Less than 3% of the leucine, methionine, serine, threonine and valine
Implications for drug design
In contrast to protein-protein targets, the design of small-molecule ligands for various enzymes has been quite successful. Unlike the reasonably large and flat interfaces seen in many protein heterodimers, most enzymes have deep pockets on their surface in which ligands can bind. The pocket is often the enzyme active site, so the rational design of inhibitors is possible without including an O-ring in the designed ligand, because the deep pocket that is provided by the enzyme presumably
Acknowledgements
A.A.B. is supported by a National Defense Science and Engineering Graduate Fellowship from the United States Department of Defense. K.S.T. is supported by a Howard Hughes Medical Institute Predoctoral Fellowship. We thank Fred Cohen, Wendell Lim and Jim Wells for helpful comments and discussion. We appreciate the comments of Warren DeLano, Marcin Joachimiak, Dave Miller and Dirk Walther. Also, we thank C. Schutt for pointing out the importance of tryptophan.
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Edited by J. Wells