Toward an energy function for the contact map representation of proteins

We analyzed several energy functions for predicting the native state of pro teins from an energy minimization procedure. We derived the parameters of a given energy function by imposing the basic requirement that the energy of the native conformation of a protein is lower than that of any conformatio n chosen from a set of decoys. Our work is motivated by a recent result whi ch proved that the simple pairwise contact approximation of the energy is i nsufficient to satisfy simultaneously such a basic requirement for all the proteins in a database, Here, we investigate the reasons of such negative r esults and show how to improve the predictive power of methods based on ene rgy minimization. We generated decoys by gapless threading, and we derive e nergy parameters by perceptron learning. We first considered hydrophobic co ntributions to the energy, defined in several ways, and showed that the add itional hydrophobic terms enlarge slightly the number of proteins that can be stabilized together. Next, we performed various modifications of the pai rwise energy term. We introduced (1) a distinction between inter-residue co ntacts on the surface and in the core of a protein and (2) a simple distanc e-dependent pairwise interaction in which a two-tier definition of contact replaces the original (single-tier) one. Our results suggest that a detaile d treatment of the pairwise potential is likely to be more relevant than th e consideration of other forces. (C) 2000 Wiley-Liss, inc.