S. Penel et Aj. Doig, Rotamer strain energy in protein helices quantification of a major force opposing protein folding, J MOL BIOL, 305(4), 2001, pp. 961-968
It is widely believed that the dominant force opposing protein folding is t
he entropic cost of restricting internal rotations. The energetic changes f
rom restricting side-chain torsional motion are more complex than simply a
loss of conformational entropy, however. A second force opposing protein fo
lding arises when a side-chain in the folded state is not in its lowest-ene
rgy rotamer, giving rotameric strain. chi strain energy results from a dihe
dral angle being shifted from the most stable conformation of a rotamer whe
n a protein folds. We calculated the energy of a side-chain as a function o
f its dihedral angles in a poly(Ala) helix. Using these energy profiles, we
quantify conformational entropy, rotameric strain energy and chi strain en
ergy for all 17 amino acid residues with sidechains in alpha -helices. We c
an calculate these terms for any amino acid in a helix interior in a protei
n, as a function of its side-chain dihedral angles, and have implemented th
is algorithm on a web page. The mean change in rotameric strain energy on f
olding is 0.42 kcal mol(-1) per residue and the mean chi strain energy is 0
.64 kcal mol(-1) per residue. Loss of conformational entropy opposes foldin
g by a mean of 1.1 kcal mol(-1) per residue, and the mean total force oppos
ing restricting a side-chain into a helix is 2.2 kcal mol(-1). Conformation
al entropy estimates alone therefore greatly underestimate the forces oppos
ing protein folding. The introduction of strain when a protein folds should
not be neglected when attempting to quantify the balance of forces affecti
ng protein stability. Consideration of rotameric strain energy may help the
use of rotamer libraries in protein design and rationalise the effects of
mutations where side-chain conformations change. (C) 2001 Academic Press.