Systematic Quantum Mechanical Region Determination in QM/MM Simulation

Hybrid
quantum mechanical-molecular mechanical (QM/MM) simulations
are widely used in enzyme simulation. Over ten convergence studies
of QM/MM methods have revealed over the past several years that key
energetic and structural properties approach asymptotic limits with
only very large (ca. 500–1000 atom) QM regions. This slow convergence
has been observed to be due in part to significant charge transfer
between the core active site and the surrounding protein environment,
which cannot be addressed by improvement of MM force fields or the
embedding method employed within QM/MM. Given this slow convergence,
it becomes essential to identify strategies for the most atom-economical
determination of optimal QM regions and to gain insight into the crucial
interactions captured only in large QM regions. Here, we extend and
develop two methods for quantitative determination of QM regions.
First, in the charge shift analysis (CSA) method, we probe the reorganization
of electron density when core active site residues are removed completely,
as determined by large-QM region QM/MM calculations. Second, we introduce
the highly parallelizable Fukui shift analysis (FSA), which identifies
how core/substrate frontier states are altered by the presence of
an additional QM residue in smaller initial QM regions. We demonstrate
that the FSA and CSA approaches are complementary and consistent on
three test case enzymes: catechol O-methyltransferase, cytochrome
P450cam, and hen eggwhite lysozyme. We also introduce validation strategies
and test the sensitivities of the two methods to geometric structure,
basis set size, and electronic structure methodology. Both methods
represent promising approaches for the systematic, unbiased determination
of quantum mechanical effects in enzymes and large systems that necessitate
multiscale modeling.