Empirical correlation for the replacement of Ala by Gly: Importance of amino acid secondary intrinsic propensities

A series of Ala vs. Gly mutations at different helical and nonhelical positions of the chemotactic protein CheY, from E. coli, has been made. We have used this information to fit a general analytical equation that describes the free energy changes of an Ala to Gly mutation within ±0.45 kcal mol^?1 with 95% confidence. The equation includes three terms: (1) the change in solvent-accessible hydrophobic surface area, corrected for the possible closure of the cavity left by deleting the C_β of the Ala; (2) the change in hydrophilic area of the nonintramolecularly hydrogen-bonded groups; and (3) the dihedral angles of the position being mutated. This last term extends the calculation to any conformation, not only α-helices. The general applicability of the equation for Ala vs. Gly mutations, when Ala or a small solvent-exposed polar residue is the wild-type residue, has been tested using data from other proteins: barnase, CI2 trypsin inhibitor, T4 lysozyme, and Staphylococcus nuclease. The predictive power of this simple approach offers the possibility of extending it to more complex mutations. © 1995 Wiley-Liss, Inc.