UCMB CP 160/16 , ave. F. Roosevelt, Universite Libre de Bruxelles, Belgium
Amino acid substitutions in peptides and proteins lead to stability changes that can be measured experimentally by the change in folding free energy. Our purpose is to evaluate these free energy variations using effective potentials derived from known protein structures. Various types of potentials are tested, and their performance is evaluated by correlating the computed free energy changes with the measured ones. Only single site mutations are considered, assumed to keep the backbone structure unperturbed. The potentials based on backbone torsion angle propensities are found to be very efficient in evaluating stability changes of solvent accessible mutations, thereby suggesting that local interactions along the chain dominate at the protein surface. The only mutations that do not correlate well seem to cause modifications of the backbone structure or of the denatured state. On the other hand, distance dependent residue-residue potentials, which are dominated by hydrophobic interactions, are found to better evaluate the stability changes of mutations buried in the protein core. The prediction accuracy is highest for completely buried residues. The influence on the correlation of various parameters used to define the potentials, and of the experimental conditions used for measuring the folding free energy changes, is analyzed.