Analysis of the Interactions Taking Place in the Recognition Site of a Bimetallic Mg(II)−Zn(II) Enzyme, Isopentenyl Diphosphate Isomerase. A Parallel Quantum-Chemical and Polarizable Molecular Mechanics Study

Abstract

Using the SIBFA polarizable molecular mechanics procedure, we analyze the binding energy of a bimetallic Mg(II)/Zn(II) enzyme, isopentenyl diphosphate isomerase, to an inhibitor built up of a trianionic diphosphate and of a cationic ethyldimethylammonium (EDMA) moiety. The analyses are performed on the protein recognition site, which totals 13 residues, as well as on some "mutants" in which one selected residue is removed at a time. They are also carried out for the individual recognition sites, namely, EDMA, Mg(II), and Zn(II). Comparisons are done with ab initio quantum chemistry (QC) results on all considered sites, with different basis sets and at different levels of correlation. The SIBFA computations reproduce the evolutions of the QC interaction energies in the recognition site and its "mutants". For such sites, small (<2-3%) relative errors are found after the BSSE correction is done. Such close agreements can conceal, however, some shortcomings found in the individual binding sites, which QC energy decomposition analyses can identify.

Polarizable molecular mechanics studies ofCu(I)/Zn(II)superoxide dismutase: Bimetallic binding site and structured waters

“…The relative errors are less than 2% in four out of the six complexes and 3% in two ones, b and c. There are nevertheless some compensation of errors, notably regarding Coulomb energy (EC), which is slightly overestimated by E MTP , and E pol , which is underestimated in SIBFA. Similar effects were previously reported but never prevented close agreements between the SIBFA and QM total interaction energies, the relative errors being <3%. It is also seen that E pol (Cu) for SIBFA, which is dominated by the quadrupolar polarizability, matches closely E pol (Cu) from RVS in all four Cu complexes.…”

“…Along with the two metal cations, it is made out of six His residues, one Zn‐bound Asp residue, and a Cu‐bound water. As in our preceding papers, the His and Asp residues are represented by imidazole and formate, respectively. The binding site is shown in Figure .…”

Quantum‐chemistry based calibration of the alkali metal cation series (Li+Cs+) for large‐scale polarizable molecular mechanics/dynamics simulations

“…Both trends were previously shown for H-bonded complexes and the complexes of ligands with metal cations including transition metal cations. [65,66] We also plan, using Monte-Carlo approaches, to resume simulations on the complexes of these cations with macromolecular hosts to try and unravel the determinants of selectivity. We plan to address selectivity issues at the entrance of ion channels.…”

“…A complex interplay of cooperativity and anticooperativity comes into play in metalloproteins, such as superoxide dismutase which has a bimetallic core on the one hand and on the other hand a dense water network in its vicinity. However, validation of SIBFA with respect to QC calculations have been reported on complexes of the recognition sites in metalloenzymes, [65,66] which could encompass up to 300 atoms. Such an interplay can be anticipated in ionic channels as well.…”

Addressing the Issues of Non-isotropy and Non-additivity in the Development of Quantum Chemistry-Grounded Polarizable Molecular Mechanics

“…One of the most attractive fields of APMM applications is ligandprotein complexes. There have been published applications regarding kinases [94] and metalloproteins [88,105,[117][118][119]. It could be rewarding to adapt Free Energy Perturbation (FEP) methods [120] or non-equilibrium MD [121] to such targets, and particularly metalloproteins, on account of the demonstrated reliable handling of metal cation-ligand interactions.…”