Quinone outside inhibitors (QoIs), which inhibit the mitochondrial respiratory system by binding to the Qo site of Complex III in fungi, are widely used as pesticides with broad spectrum antifungal activity. However, excessive use of QoIs leads to pesticide resistance through mutation of amino acid residues in the Qo site. Recently, metyltetraprole, a novel QoI that is effective against wild-type and resistant mutant fungi, was developed. Interestingly, metyltetraprole has a very similar structure to other QoIs, azoxystrobin and pyraclostrobin, which do not act on resistant mutants. However, it is unknown how slight structural differences in these inhibitors alter their effectiveness towards fungi with amino acid mutations in the Qo site of Complex III. Therefore, we studied the features of interactions of inhibitors effective towards resistant mutants by quantitatively comparing the interaction profiles of three QoIs at the atomic level. First, we reproduced the binding affinity by the thermodynamic integration (TI) method, which treated explicitly environmental molecules and considered the pseudo-binding pathway. As such, a good correlation (R2 = 0.74) was observed between the binding free energy calculated using the TI method and experimentally observed pIC50 value in 12 inhibitor-target pairs, including wild-type and mutant Complex III in two fungal species, Zymoseptoria tritici and Pyrenophora teres. Trajectory analysis of this TI calculation revealed that the effectiveness against resistant mutant fungi strongly depended on the interaction of constituent parts of the inhibitor disposed near the active center of the target protein. Specifically, the key in the effectiveness against resistant mutant fungi is that the corresponding component part, tetrazolinone moiety of metyltetraprole, traded off Coulomb and van der Waals interactions in response to subtle changes in the binding pose.
The co-solvent effect on the proton transfer reaction of glycine in a water-acetonitrile mixture was examined using the reference interaction-site model self-consistent field theory. The free energy profiles of the proton transfer reaction of glycine between the carboxyl oxygen and amino nitrogen were computed in a water-acetonitrile mixture solvent at various molar fractions. Two types of reactions, the intramolecular proton transfer and water-mediated proton transfer, were considered. In both types of the reactions, a similar tendency was observed. In the pure water solvent, the zwitterionic form, where the carboxyl oxygen is deprotonated while the amino nitrogen is protonated, is more stable than the neutral form. The reaction free energy is -10.6 kcal mol(-1). On the other hand, in the pure acetonitrile solvent, glycine takes only the neutral form. The reaction free energy from the neutral to zwitterionic form gradually increases with increasing acetonitrile concentration, and in an equally mixed solvent, the zwitterionic and neutral forms are almost isoenergetic, with a difference of only 0.3 kcal mol(-1). The free energy component analysis based on the thermodynamic cycle of the reaction also revealed that the free energy change of the neutral form is insensitive to the change of solvent environment but the zwitterionic form shows drastic changes. In particular, the excess chemical potential, one of the components of the solvation free energy, is dominant and contributes to the stabilization of the zwitterionic form.
A scheme for quantitatively computing the acid dissociation constant, pKa, of hydrated molecules is proposed. It is based on the three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) theory coupled with the linear fitting correction (LFC) scheme. In LFC/3D-RISM-SCF, pKa values of target molecules are evaluated using the Gibbs energy difference between the protonated and unprotonated states calculated by 3D-RISM-SCF and the parameters fitted by the LFC scheme to the experimental values of training set systems. The pKa values computed by LFC/3D-RISM-SCF show quantitative agreement with the experimental data.
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