We. Stites et J. Pranata, EMPIRICAL-EVALUATION OF THE INFLUENCE OF SIDE-CHAINS ON THE CONFORMATIONAL ENTROPY OF THE POLYPEPTIDE BACKBONE, Proteins, 22(2), 1995, pp. 132-140
Changes in amino acid side chains have long been recognized to alter t
he range and distribution of phi, psi angles found in the main chain o
f polypeptides. Altering the range and distribution of phi, psi angles
also alters the conformational entropy of the flexible denatured stat
e and may thus stabilize or destabilize it relative to the comparative
ly conformationally rigid native state. A database of 12,320 residues
from 61 nonhomologous, high resolution crystal structures was examined
to determine the phi, psi conformational preferences of each of the 2
0 amino acids. These observed distributions in the native state of pro
teins are assumed to also reflect the distributions found in the denat
ured state. The distributions were used to approximate the energy surf
ace for each residue, allowing the calculation of relative conformatio
nal entropies for each residue relative to glycine, In the most extrem
e case, replacement of glycine by proline, conformational entropy chan
ges will stabilize the native state relative to the denatured state by
-0.82 +/- 0.08 kcaYmol at 20 degrees C. Surprisingly, alanine is foun
d to be the most ordered residue other than proline. This unexpected r
esult is a result of the high percentage of alanines found in helical
conformations. This either indicates that the observed distributions i
n the native state do not reflect the distributions in the denatured s
tate, or that alanine is much more likely to adopt a helical conformat
ion in the denatured state than residues with longer side chains. Amon
g those residues with phi, psi angles compatible with helix incorporat
ion the percentage of alanines actually in helices is very similar to
other residues. This and the consistent ordering of alanine relative t
o other residues regardless of secondary structure are evidence that p
hi, psi distributions in native states reflect those in the denatured
states. (C) 1995 Wiley-Liss, Inc.