Calculation of affinities of peptides for proteins

Several methodologies were employed to calculate the Gibbs standard free energy of binding for a collection of protein-ligand complexes, where the ligand is a peptide and the protein is representative for various protein families. Almost 40 protein-ligand complexes were employed for a continuum approach, which considers the protein and the peptide at the atomic level, but includes solvent as a polarizable continuum. Five protein-ligand complexes were employed for an all-atom approach that relies on a combination of the double decoupling method with thermodynamic integration and molecular dynamics. These affinities were also computed by means of the linear interaction energy method. Although it generally proved rather difficult to predict the absolute free energies correctly, for some protein families the experimental ranking order was correctly reproduced by the continuum and all-atom approach. Considerable attention has also been given to correctly analyze the affinities of charged peptides, where it is required to judge the effect of one or more ions that are being decoupled in an all-atom approach to preserve electroneutrality. The various methods are further judged upon their merits.