Comparison of protein–protein interactions in serine protease‐inhibitor and antibody‐antigen complexes: Implications for the protein docking problem

Publisher Website
Google Scholar
Abstract
The protein‐protein interaction energy of 12 nonhomologous serine protease‐inhibitor and 15 antibody‐antigen complexes is calculated using a molecular mechanics formalism and dissected in terms of the main‐chain vs. side‐chain contribution, nonrotameric side‐chain contributions, and amino acid residue type involvement in the interface interaction.There are major differences in the interactions of the two types of protein‐protein complex. Protease‐inhibitor complexes interact predominantly through a main‐chain‐main‐chain mechanism while antibody‐antigen complexes interact predominantly through a side‐chain‐side‐chain or a side‐chain‐main‐chain mechanism. However, there is no simple correlation between the main‐chain‐main‐chain interaction energy and the percentage of main‐chain surface area buried on binding. The interaction energy is equally effected by the presence of nonrotameric side‐chain conformations, which constitute ∼20% of the interaction energy. The ability to reproduce the interface interaction energy of the crystal structure if original side‐chain conformations are removed from the calculation is much greater in the protease‐inhibitor complexes than the antibody‐antigen complexes. The success of a rotameric model for protein‐protein docking appears dependent on the extent of the main‐chain‐main‐chain contribution to binding.Analysis of (1) residue type and (2) residue pair interactions at the interface show that antibody‐antigen interactions are very restricted with over 70% of the antibody energy attributable to just six residue types (Tyr > Asp > Asn > Ser > Glu > Trp) in agreement with previous studies on residue propensity. However, it is found here that 50% of the antigen energy is attributable to just four residue types (Arg = Lys > Asn > Asp). On average just 12 residue pair interactions (6%) contribute over 40% of the favorable interaction energy in the antibody‐antigen complexes, with charge‐charge and charge/polar‐tyrosine interactions being prominent. In contrast protease inhibitors use a diverse set of residue types and residue pair interactions.