We develop a protocol for estimating the free energy
difference between different conformations of the same
polypeptide chain. The conformational free energy evaluation
combines the CHARMM force field with a continuum treatment
of the solvent. In almost all cases studied, experimentally
determined structures are predicted to be more stable than
misfolded “decoys.” This is due in part to
the fact that the Coulomb energy of the native protein
is consistently lower than that of the decoys. The solvation
free energy generally favors the decoys, although the total
electrostatic free energy (sum of Coulomb and solvation
terms) favors the native structure. The behavior of the
solvation free energy is somewhat counterintuitive and,
surprisingly, is not correlated with differences in the
burial of polar area between native structures and decoys.
Rather, the effect is due to a more favorable charge distribution
in the native protein, which, as is discussed, will tend
to decrease its interaction with the solvent. Our results
thus suggest, in keeping with a number of recent studies,
that electrostatic interactions may play an important role
in determining the native topology of a folded protein.
On this basis, a simplified scoring function is derived
that combines a Coulomb term with a hydrophobic contact
term. This function performs as well as the more complete
free energy evaluation in distinguishing the native structure
from misfolded decoys. Its computational efficiency suggests
that it can be used in protein structure prediction applications,
and that it provides a physically well-defined alternative
to statistically derived scoring functions.