Energy-Screened Many-Body Expansion for Protein-Ligand Interactions: Examining Convergence for Metalloenzymes Through Seven-Body Interactions.

Fragment-based quantum chemistry is a powerful strategy for calculating protein-ligand interaction energies using quantum chemistry methods. Rigorous convergence often requires hundreds of atoms in the protein binding-site model, especially if that model is constructed using distance-based criteria to select amino acid residues, while three- and four-body calculations exhibit instability related to combinatorial proliferation in the number of subsystem calculations. Here, we report an energy-based screening protocol for the many-body expansion applied to protein-ligand interactions, implemented in the open-source Fragme∩t code. Using a combination of aggressive screening based on semiempirical quantum chemistry, with an improved graph-theoretical algorithm to eliminate unimportant subsystems, we are able to perform -body calculations up to = 7 using density functional theory in triple-ζ basis sets. Distance cutoffs further reduce the cost without compromising accuracy. Rapid and stable convergence of the many-body expansion is obtained by = 4, for a pair of metalloenzymes in which a divalent ion coordinates directly to the ligand. As compared to previous results that relied solely on distance cutoffs, oscillations in the -body corrections are reduced or eliminated, although residual errors remain in one case. This work demonstrates that benchmark-quality protein-ligand interaction energies can be systematically converged using a method with excellent parallel efficiency and scalability.