Hybrid quantum mechanical/molecular mechanical (QM/MM)
simulations
fuel discoveries in many fields of science including computational
biochemistry and enzymology. Development of more convenient tools
leads to an increase in the number of works in which mechanical insights
into enzymes’ mode of operation are obtained. Most commonly,
these tools feature hydrogen-capping (link atom) approach to provide
coupling between QM and MM subsystems across a covalent bond. Extensive
studies were conducted to provide a solid foundation for the correctness
of such an approach when a bond to a nonpolar MM atom is considered.
However, not every task may be accomplished this way. Certain scenarios
of using QM/MM in computational enzymology encourage or even necessitate
the incorporation of backbone atoms into the QM region. Two out of
three backbone atoms are polar, and in QM/MM with electrostatic embedding,
a neighboring link atom will be hyperpolarized. Several schemes to
mitigate this effect were previously proposed alongside a rigorous
assessment of quantitative effects on model systems. However, it was
not clear whether they may translate into qualitatively different
results and how link atom hyperpolarization may manifest itself in
a real-life enzymological scenario. Here, we show that the consequences
of such an artifact may be severe and may completely overturn the
conclusions drawn from the simulations. Our case advocates for the
use of charge redistribution schemes whenever intra-backbone QM/MM
boundaries are considered. Moreover, we addressed how different boundary
types and charge redistribution schemes influence backbone dynamics.
We showed that the results are heavily dependent on which boundary
MM terms are retained, with charge alteration being of secondary importance.
In the worst case, only three intra-backbone boundaries may be used
with relative confidence in the adequacy of resulting simulations,
irrespective of the hyperpolarization mitigation scheme. Thus, advances
in the field are certainly needed to fuel new discoveries. As of now,
we believe that issues raised in this work might encourage authors
in the field to report what boundaries, boundary MM terms, and charge
redistribution schemes they are using, so their results may be correctly
interpreted.
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