Two Rules on the Protein-Ligand Interaction

So far, we still lack a clear molecular mechanism to explain the protein-ligand interaction on the basis of electronic structure of a protein. By combining the calculation of the full electronic structure of a protein along with its hydrophobic pocket and the perturbation theory, we found out two rules on the protein-ligand interaction. One rule is that the interaction only occurs between the lowest unoccupied molecular orbitals (LUMOs) of a protein and the highest occupied molecular orbital (HOMO) of its ligand, not between the HOMOs of a protein and the LUMO of its ligand. The other rule is that only those residues or atoms located in both the LUMOs of a protein and a surface pocket of a protein are active residues or active atoms of the protein and the corresponding pocket is the ligand binding site. These two rules are derived from the structure of energy levels of a protein and could be one of important criterions of the drug design. They were validated on complex CypA/CsA and FKBP12/FK506. Furthermore, a tripeptide Ala-Gly-Pro (AGP) was predicted to bind to CypA as an application of our two rules. And the biological assays results show that AGP has the same order of binding affinity and inhibition of PPIase activity as CsA.