Protein Engineering, Vol. 15, No. 7, 555-560,
July 2002
© 2002 Oxford University Press
Identification of amino acids involved in protein structural uniqueness: implication for de novo protein design
1 The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, 3 National Institute of Genetics, Mishima, Shizuoka 411-8540, 4 Department of Physics, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo 170-0031 and 6 Department of Life Sciences, Faculty of Science, Himeji Institute of Technology, Ako-gun,Hyogo 678-1297, Japan
Structural uniqueness is characteristic of native proteins and is essential to express their biological functions. The major factors that bring about the uniqueness are specific interactions between hydrophobic residues and their unique packing in the protein core. To find the origin of the uniqueness in their amino acid sequences, we analyzed the distribution of the side chain rotational isomers (rotamers) of hydrophobic amino acids in protein tertiary structures and derived 
Scontact, the conformational-entropy changes of side chains by residue–residue contacts in each secondary structure. The Scontact values indicate distinct tendencies of the residue pairs to restrict side chain conformation by inter-residue contacts. Of the hydrophobic residues in 
-helices, aliphatic residues (Leu, Val, Ile) strongly restrict the side chain conformations of each other. In ß-sheets, Met is most strongly restricted by contact with Ile, whereas Leu, Val and Ile are less affected by other residues in contact than those in -helices. In designed and native protein variants, Scontact was found to correlate with the folding–unfolding cooperativity. Thus, it can be used as a specificity parameter for designing artificial proteins with a unique structure.