Thermochemical and Quantum Descriptor Calculations for Gaining Insight into Ricin Toxin A (RTA) Inhibitors

Abstract

In this work, we performed a study to assess the interactions between the ricin toxin A (RTA) subunit of ricin and some of its inhibitors using modern semiempirical quantum chemistry and ONIOM quantum mechanics/molecular mechanics (QM/MM) methods. Two approaches were followed (calculation of binding enthalpies, Δ H bind , and reactivity quantum chemical descriptors) and compared with the respective half-maximal inhibitory concentration (IC 50 ) experimental data, to gain insight into RTA inhibitors and verify which quantum chemical method would better describe RTA–ligand interactions. The geometries for all RTA–ligand complexes were obtained after running classical molecular dynamics simulations in aqueous media. We found that single-point energy calculations of Δ H bind with the PM6-DH+, PM6-D3H4, and PM7 semiempirical methods and ONIOM QM/MM presented a good correlation with the IC 50 data. We also observed, however, that the correlation decreased significantly when we calculated Δ H bind after full-atom geometry optimization with all semiempirical methods. Based on the results from reactivity descriptors calculations for the cases studied, we noted that both types of interactions, molecular overlap and electrostatic interactions, play significant roles in the overall affinity of these ligands for the RTA binding pocket.

Enantiopurification of Mandelic Acid by Crystallization-Induced Diastereomer Transformation: An Experimental and Computational Study

“…We used the BFGS algorithm for the full relaxation (both lattice and atomic position optimizations) of the crystal structure. Using the DFT-optimized structures, we calculated the lattice energies via the semiempirical PM7 method as implemented in MOPAC v2016 which has been shown to have good performance in predicting thermodynamic properties particularly for organic systems. , To validate the calculated lattice energies, we compared the experimental melting point against the melting point computed from the lattice energy using the simple model of Salahinejad et al This model assumes a linear relationship between the ratio of enthalpy of sublimation to the melting point (Δ H sub / T m ) against the number of rotatable bonds …”

Separation of Etiracetam Enantiomers Using Enantiospecific Cocrystallization with 2-Chloromandelic Acid

“…The generated unit cells were then optimized using the semiempirical PM7 Hamiltonian with periodic boundary conditions as implemented in MOPAC v2016, 29 , 30 which has been shown to have good performance in predicting thermodynamic properties particularly for organic systems. 31 , 32 The structures of the five most stable candidates were further refined using periodic density functional theory (DFT) calculations as implemented in the CP2K package, 33 which uses a mixed Gaussian/plane-wave (GPW) basis set. The exchange and correlation energies were evaluated using the semilocal Perdew–Burke–Ernzerhof (PBE) form of the generalized gradient approximation (GGA) functional together with Grimme’s D3 van der Waals correction.…”

“…To reduce the computational cost, we constrained the search space to the most common space groups for chiral cocrystals, i.e., P 1, P -1, P2, P 21, P 21/ c , and P 212121. The generated unit cells were then optimized using the semiempirical PM7 Hamiltonian with periodic boundary conditions as implemented in MOPAC v2016, , which has been shown to have good performance in predicting thermodynamic properties particularly for organic systems. , The structures of the five most stable candidates were further refined using periodic density functional theory (DFT) calculations as implemented in the CP2K package, which uses a mixed Gaussian/plane-wave (GPW) basis set. The exchange and correlation energies were evaluated using the semilocal Perdew–Burke–Ernzerhof (PBE) form of the generalized gradient approximation (GGA) functional together with Grimme’s D3 van der Waals correction. , DZVP-MOLOPT basis sets and Goedecker–Teter–Hutter (GTH) pseudopotentials were selected in the calculations. , An energy cutoff of 500 Ry and relative energy cutoff of 80 Ry were found to be sufficient for energy convergence.…”

Lessons Learned from Semiempirical Methods for the Li-Ion Battery Solid Electrolyte Interphase

“…1−5 However, due to the limitation of the experimental techniques, it is challenging to investigate other properties of the SEI like thermodynamics and kinetics of its formation and growth. [1][2][3]5,6 To fill this knowledge gap, computational models have emerged to better understand the SEI formation and growth. Previous theoretical studies (e.g., DFT) focused on the decomposition pathways of main electrolyte species, i.e., the ethylene carbonate solvent and the supporting salt lithium hexafluorophosphate, LiPF 6 .…”

“…For example, Rocha-Santos et al have used PM6 and PM7 methods to gain insights into the binding energies of various ligand/protein complexes. 6 In the context of lithium-ion batteries, a study performed by Kim et al has compared the performance of various semiempirical methods based on the Hartree−Fock methods to investigate the electronic properties of various solvents used in lithium-ion batteries. 14 They found that PM#-based methods showed better agreement with DFT reference data.…”