A protein interaction free energy model based on amino acid residue contributions: Assessment of point mutation stability of T4 lysozyme

Here we present a model to estimate the interaction free energy contribution of each amino acid residue of a given protein. Protein interaction energy is described in terms of per-residue interaction factors, mu. Multibody interactions are implicitly captured in mu through the combination of amino acid terms (gamma) guided by local conformation indices (sigma). The model enables construction of an interaction factor heat map for a protein in a given fold, allows prima facie assessment of the degree of residue-residue interaction, and facilitates a qualitative and quantitative evaluation of protein association properties. The model was used to compute thermal stability of T4 bacteriophage lysozyme mutants across seven sites. Qualitative assessment of mutational effects provides a straightforward rationale regarding whether a particular site primarily perturbs native or non-native states, or both. The presented model was found to be in good agreement with experimental mutational data (R-2= 0.73) and suggests an approach by which to convert structure space into energy space.