Structure-based conformational preferences of amino acids

Proteins can he very tolerant to amino acid substitution, even within their core. Understanding the factors responsible for this behavior is of critic al importance for protein engineering and design. Mutations in proteins hav e been quantified in terms of the changes in stability they induce. For exa mple, guest residues in specific secondary structures have been used as pro bes of conformational preferences of amino acids, yielding propensity scale s. Predicting these amino acid propensities would be a good test of any new potential energy functions used to mimic protein stability. We have recent ly developed a protein design procedure that optimizes whale sequences for a given target conformation based on the knowledge of the template backbone and on a semiempirical potential energy function. This energy function is purely physical, including steric interactions based on a Lennard-Jones pot ential, electrostatics based on a Coulomb potential, and hydrophobicity in the form of an environment free energy based on accessible surface area and interatomic: contact areas. Sequences designed by this procedure for 10 di fferent proteins were analyzed to extract conformational preferences for am ino acids. The resulting structure-based propensity scales show significant agreements with experimental propensity scale values, both for cr-helices and P-sheets. These results indicate that amino acid conformational prefere nces are a natural consequence of the potential energy we use. This confirm s the accuracy of our potential and indicates that such preferences should not be added as a design criterion.