Combining Evolutionary Conservation and Quantum Topological Analyses To Determine Quantum Mechanics Subsystems for Biomolecular Quantum Mechanics/Molecular Mechanics Simulations

Selection of residues and other molecular
fragments for inclusion
in the quantum mechanics (QM) region for QM/molecular mechanics (MM)
simulations is an important step for these calculations. Here, we
present an approach that combines protein sequence/structure evolution
and electron localization function (ELF) analyses. The combination
of these two analyses allows the determination of whether a residue
needs to be included in the QM subsystem or can be represented by
the MM environment. We have applied this approach on two systems previously
investigated by QM/MM simulations, 4-oxalocrotonate tautomerase (4OT)
and ten-eleven translocation-2 (TET2), that provide examples where
fragments may or may not need to be included in the QM subsystem.
Subsequently, we present the use of this approach to determine the
appropriate QM subsystem to calculate the minimum energy path (MEP)
for the reaction catalyzed by human DNA polymerase λ (Polλ)
with a third cation in the active site. Our results suggest that the
combination of protein evolutionary and ELF analyses provides insights
into residue/molecular fragment selection for QM/MM simulations.