Journal of Computational Chemistry

doi: 10.1002/jcc.26651pmid: N/A

Walker, Brandon; Liu, Chengwen; Wait, Elizabeth; Ren, Pengyu

doi: 10.1002/jcc.26954pmid: 35778723

A next‐generation protocol (Poltype 2) has been developed which automatically generates AMOEBA polarizable force field parameters for small molecules. Both features and computational efficiency have been drastically improved. Notable advances include improved database transferability using SMILES, robust torsion fitting, non‐aromatic ring torsion parameterization, coupled torsion‐torsion parameterization, Van der Waals parameter refinement using ab initio dimer data and an intelligent fragmentation scheme that produces parameters with dramatically reduced ab initio computational cost. Additional improvements include better local frame assignment for atomic multipoles, automated formal charge assignment, Zwitterion detection, smart memory resource defaults, parallelized fragment job submission, incorporation of Psi4 quantum package, ab initio error handling, ionization state enumeration, hydration free energy prediction and binding free energy prediction. For validation, we have applied Poltype 2 to ~1000 FDA approved drug molecules from DrugBank. The ab initio molecular dipole moments and electrostatic potential values were compared with Poltype 2 derived AMOEBA counterparts. Parameters were further substantiated by calculating hydration free energy (HFE) on 40 small organic molecules and were compared with experimental data, resulting in an RMSE error of 0.59 kcal/mol. The torsion database has expanded to include 3543 fragments derived from FDA approved drugs. Poltype 2 provides a convenient utility for applications including binding free energy prediction for computational drug discovery. Further improvement will focus on automated parameter refinement by experimental liquid properties, expansion of the Van der Waals parameter database and automated parametrization of modified bio‐fragments such as amino and nucleic acids.

Gorantla, Sai Manoj N. V. T.; Mondal, Kartik Chandra

doi: 10.1002/jcc.26956pmid: 35861589

Arenes [C6H3R(TMS)(OTf); also called benzyne/aryne precursors] containing inter‐related leaving groups Me3Si (TMS) and CF3SO3(OTf) on the adjacent positions (1,2‐position) are generally converted to their corresponding aryne‐intermediates via the addition of fluoride anion (F−) and subsequent elimination of TMS and OTf groups. This reaction is believed to proceed via the formation of an anionic intermediate [C6H4(TMS‐F)(OTf)]−. The EDA‐NOCV analysis (EDA‐NOCV = energy decomposition analysis‐natural orbital for chemical valence) of over 35 such precursors of varied types have been reported to reveal bonding and stability of CArSi and COTf bonds. EDA‐NOCV showed that the nature of the CArSi bond of C6H3R(TMS)(OTf) can be expressed as both dative and electron sharing [CArSi, CAr→Si]. The CArOTf bond, on the other hand, can be described explicitly as dative [CAr←OTf]. The nature of CArSi bond of [C6H4(TMS‐F)(OTf)]− exclusively changes to covalent dative σ‐bond CAr→S(Me)3F on the attachment of F− to the TMS group of C6H4(TMS)(OTf). Introduction of σ‐electron withdrawing group (like OMe, NMe2, and NO2) to the ortho‐position of the TMS group of functionalized arynes C6H3R(TMS)(OTf) prefer to have a covalent dative σ‐bond (CAr→Si) over an electron‐sharing covalent σ‐bond (CArSi). If this σ‐electron withdrawing group is shifted from ortho‐position to meta‐ and para‐positions, then the preference for a dative bond decreases significantly, implying that the electronic effect on the nature of chemical bonds affects through bond paths. This effect dies with distance, similar to the well‐known inductive effect.

Curtolo, Felipe; Arantes, Guilherme M.

doi: 10.1002/jcc.26957pmid: 35778728

Flavins are employed as redox cofactors and chromophores in a plethora of flavoenzymes. Their versatility is an outcome of intrinsic molecular properties of the isoalloxazine ring modulated by the protein scaffold and surrounding solvent. Thus, an investigation of isolated flavins with high‐level electronic‐structure methods and with error assessment of the calculated properties will contribute to building better models of flavin reactivity. Here, we benchmarked ground‐state properties such as electron affinity, gas‐phase basicity, dipole moment, torsion energy, and tautomer stability for lumiflavins in all biologically relevant oxidation and charge states. Overall, multiconfigurational effects are small and chemical accuracy is achieved by coupled‐cluster treatments of energetic properties. Augmented basis sets and extrapolations to the complete basis‐set limit are necessary for consistent agreement with experimental energetics. Among DFT functionals tested, M06‐2X shows the best performance for most properties, except gas‐phase basicity, in which M06 and CAM‐B3LYP perform better. Moreover, dipole moments of radical flavins show large deviations for all functionals studied. Tautomers with noncanonical protonation states are significantly populated at normal temperatures, adding to the complexity of modeling flavins. These results will guide future computational studies of flavoproteins and flavin chemistry by indicating the limitations of electronic‐structure methodologies and the contributions of multiple tautomeric states.

Campos‐Fernández, Linda; Ortiz‐Muñiz, Rocío; Cortés‐Barberena, Edith; Mares‐Sámano, Sergio; Garduño‐Juárez, Ramón; Soriano‐Correa, Catalina

doi: 10.1002/jcc.26959pmid: 35796405

Chagas disease is caused by Trypanosoma cruzi. Benznidazole and nifurtimox are drugs used for its therapy; nevertheless, they have collateral effects. NADH‐fumarate (FUM) reductase is a potential pharmacological target since it is essential for survival of parasite and is not found in humans. The objectives are to design and characterize the electronic structure of imidazole and nitroimidazole derivatives at DFT‐M06‐2X level in aqueous solution; also, to model the NADH‐FUM reductase and analyze its intermolecular interactions by molecular docking. Quantum‐chemical descriptors allowed to select the molecules with the best physicochemical properties and lowest toxicity. A high‐quality three‐dimensional structure of NADH‐FUM reductase was obtained by homology modeling. Water molecules do not have influence in the interaction between FUM and NADH‐FUM reductase. The main hydrogen‐binding interactions for FUM were identified in NADH, Lys172, and Arg89; while hydrophobic interactions in Phe479, Thr174, Met63. The molecules S3‐8, S2‐8, and S1‐8 could be inhibitors of NADH‐FUM reductase.

Afonin, Andrei V.; Rusinska‐Roszak, Danuta

doi: 10.1002/jcc.26960pmid: 35851685

Both the experimental and calculated data reveal that a strong NH⋯OС intramolecular hydrogen bond closing the seven‐membered quasi‐cycle is formed in the Z‐isomers of pyrrolylenones. Comparison of the NH⋯OС intramolecular hydrogen bonds energies in the pyrrolylenones, estimated via the molecular tailoring approach, with the similar data for reference malonaldehydes shows that the resonance‐assisted hydrogen bonding occurs in both cases, the hydrogen bond energy being varied mainly within 10–20 kcal/mol. The combined application of function‐based and molecular tailoring approaches makes it possible to decompose the NH⋯OС total hydrogen bond energy in the pyrrolylenones into the π‐ and σ‐components. It is established that the contribution of the π‐component to the total N(O)H⋯OС hydrogen bond energy in the pyrrolylenones and malonaldehydes is almost the same (6–7 kcal/mol). Comparison of the π‐contribution to the total energy of the resonance‐assisted hydrogen bonding in the Z‐isomer of pyrrolylenones with the energy of the push‐pull effect in the E‐isomer of pyrrolylenones reveals that the resonance contribution to the total energy of the resonance‐assisted hydrogen bond in the former significantly enhances with reference to the net resonance energy in the latter. The appearance of the resonance‐assisted hydrogen bond in the pyrrolylenones is possible due to the participation in the interaction of 10 or 14 π‐electrons satisfying the Hückel aromaticity rule.