In order to calculate the tertiary structure of a protein from its ami
no acid sequence, the thermodynamic approach requires a potential func
tion of sequence and conformation that has its global minimum at the n
ative conformation for many different proteins. Here we study the beha
vior of such functions for the simplest model system that still has th
e essential features of the protein folding problem, namely two-dimens
ional square lattice chain configurations involving two residue types.
First we demonstrate a method for accurately recovering the given con
tact potential from only a knowledge of which sequences fold to which
structures and what the non-native structures are. Second, we show how
to derive from the same information more general potential functions
having much better positive correlations between potential function va
lue and conformational deviation from the native. These functions cons
equently permit faster and more reliable searches for the native confo
rmation, given the native sequence. Furthermore, the method for findin
g such potentials is easily applied to more realistic protein models.
(C) 1996 Academic Press Limited