Improved QM/MM Linear-Interaction Energy Model for Substrate Recognition in Zinc-Containing Metalloenzymes

One of the essential challenges in
the description of receptor–drug
interactions in the presence of various polyvalent cations (such as
zinc, magnesium, or iron) is the accurate assessment of the electronic
effects due to cofactor binding. The effects can range from partial
electronic polarization of the proximal atoms in a receptor and bound
substrate to long-range effects related to partial charge transfer
and electronic delocalization effects between the cofactor and the
drug. Here, we examine the role of the explicit account for electronic
effects for a panel of small-molecule inhibitors binding to the zinc-aminopeptidase
PfA-M1, an essential target for antimalarial drug development. Our
study on PfA-M1:inhibitor interactions at the QM level reveals that
the partial charge and proton transfer due to bound zinc ion are important
mechanisms in the inhibitors’ recognition and catalysis. The
combination of classical MD simulations with a posteriori QM/MM corrections with novel DFTB parameters for the zinc cation
and the linear-interaction energy (LIE) approach offers by far the
most accurate estimates for the PfA-M1:inhibitor binding affinities,
opening the door for future inhibitor design.