We proposed recently an optimization method to derive energy parameters for
simplified models of protein folding. The method is based on the maximizat
ion of the thermodynamic average of the overlap between protein native stru
ctures and a Boltzmann ensemble of alternative structures. Such a condition
enforces protein models whose ground states are most similar to the corres
ponding native states. We present here an extensive testing of the method f
or a simple residue-residue contact energy function and for alternative str
uctures generated by threading. The optimized energy function guarantees hi
gh stability and a well-correlated energy landscape to most representative
structures in the PDB database. Failures in the recognition of the native s
tructure can be attributed to the neglect of interactions between different
chains in oligomeric proteins or with cofactors, When these are taken into
account, only very few X-ray structures are not recognized. Most of them a
re short inhibitors or fragments and one is a structure that presents serio
us inconsistencies. Finally, we discuss the reasons that make NMR structure
s more difficult to recognize. (C) 2001 Wiley-Liss, Inc.