Quick-and-Easy Validation of Protein–Ligand Binding Models Using Fragment-Based Semiempirical Quantum Chemistry

Electronic structure calculations in enzymes converge
very slowly
with respect to the size of the model region that is described using
quantum mechanics (QM), requiring hundreds of atoms to obtain converged
results and exhibiting substantial sensitivity (at least in smaller
models) to which amino acids are included in the QM region. As such,
there is considerable interest in developing automated procedures
to construct a QM model region based on well-defined criteria. However,
testing such procedures is burdensome due to the cost of large-scale
electronic structure calculations. Here, we show that semiempirical
methods can be used as alternatives to density functional theory (DFT)
to assess convergence in sequences of models generated by various
automated protocols. The cost of these convergence tests is reduced
even further by means of a many-body expansion. We use this approach
to examine convergence (with respect to model size) of protein–ligand
binding energies. Fragment-based semiempirical calculations afford
well-converged interaction energies in a tiny fraction of the cost
required for DFT calculations. Two-body interactions between the ligand
and single-residue amino acid fragments afford a low-cost way to construct
a “QM-informed” enzyme model of reduced size, furnishing
an automatable active-site model-building procedure. This provides
a streamlined, user-friendly approach for constructing ligand binding-site
models that requires neither a priori information
nor manual adjustments. Extension to model-building for thermochemical
calculations should be straightforward.