Influence of water on protein structure. An analysis of the preferences of amino acid residues for the inside or outside and for specific conformations in a protein molecule.

The x-ray structures of 20 proteins have been examined and each of the residues in these proteins was assigned to the inside or outside of the molecules and to a conformational state. The data obtained confirm that polar groups are generally found on the outside of proteins and nonpolar residues are generally found on the inside. Seven of the amino acids (Ala, Arg, Cys, His, Pro, Ser, Tyr) have inside/outside preferences which are not consistent with their usual assignment as either polar or nonpolar residues; explanations are given for these apparent inconsistencies. Of the three types of backbone structure considered here (extended, alpha helix, and nonregular), extended structures have the greatest preference for the inside of proteins, and nonregular structures have the greatest preference for the outside. It is suggested that differences in entropy play an important part in the inside/outside preferences of backbone structures. There are generally significant changes in the conformational preferences of the residues in going from the inside to the outside of proteins; environmental (rather than local) solute-solvent interactions seem to be the predominant cause of these changes in conformational preferences.