Quantum Mechanical Molecular Models Research Articles

Discovery of putative inhibitors against main drivers of SARS-CoV-2 infection: Insight from quantum mechanical evaluation and molecular modeling.

SARS-CoV-2 triggered a worldwide medical crisis, affecting the world’s social, emotional, physical, and economic equilibrium. However, treatment choices and targets for finding a solution to COVID-19’s threat are becoming limited. A viable approach to combating the threat of COVID-19 is by unraveling newer pharmacological and therapeutic targets pertinent in the viral survival and adaptive mechanisms within the host biological milieu which in turn provides the opportunity to discover promising inhibitors against COVID-19. Therefore, using high-throughput virtual screening, manually curated compounds library from some medicinal plants were screened against four main drivers of SARS-CoV-2 (spike glycoprotein, PLpro, 3CLpro, and RdRp). In addition, molecular docking, Prime MM/GBSA (molecular mechanics/generalized Born surface area) analysis, molecular dynamics (MD) simulation, and drug-likeness screening were performed to identify potential phytodrugs candidates for COVID-19 treatment. In support of these approaches, we used a series of computational modeling approaches to develop therapeutic agents against COVID-19. Out of the screened compounds against the selected SARS-CoV-2 therapeutic targets, only compounds with no violations of Lipinski’s rule of five and high binding affinity were considered as potential anti-COVID-19 drugs. However, lonchocarpol A, diplacol, and broussonol E (lead compounds) were recorded as the best compounds that satisfied this requirement, and they demonstrated their highest binding affinity against 3CLpro. Therefore, the 3CLpro target and the three lead compounds were selected for further analysis. Through protein–ligand mapping and interaction profiling, the three lead compounds formed essential interactions such as hydrogen bonds and hydrophobic interactions with amino acid residues at the binding pocket of 3CLpro. The key amino acid residues at the 3CLpro active site participating in the hydrophobic and polar inter/intra molecular interaction were TYR54, PRO52, CYS44, MET49, MET165, CYS145, HIS41, THR26, THR25, GLN189, and THR190. The compounds demonstrated stable protein–ligand complexes in the active site of the target (3CLpro) over a 100 ns simulation period with stable protein–ligand trajectories. Drug-likeness screening shows that the compounds are druggable molecules, and the toxicity descriptors established that the compounds demonstrated a good biosafety profile. Furthermore, the compounds were chemically reactive with promising molecular electron potential properties. Collectively, we propose that the discovered lead compounds may open the way for establishing phytodrugs to manage COVID-19 pandemics and new chemical libraries to prevent COVID-19 entry into the host based on the findings of this computational investigation.

New Techniques of Structure Elucidation for Sesquiterpenes.

The most significant new techniques that have been used in the twenty-first century for the structure elucidation of sesquiterpenes and some derivatives are reviewed in this chapter. A distinctive feature of these methodologies is the combination of accurate experimental measurements with theoretical data obtained by molecular modeling calculations that allow to visualize, understand, and quantify many structural characteristics. This has been the case for NMR spectroscopy, which has expanded its potential for solving complex structural problems by means of comparison with quantum mechanical molecular models. Ab initio and density functional theory calculations of chemical shifts, coupling constants, and residual chemical shift anisotropies have played important roles in the solution of many structures of sesquiterpenes. The assignments of their absolute configurations by evaluation of calculated and experimental chiroptical properties as electronic and vibrational circular dichroism are also reviewed. This chapter also includes the use of X-ray diffraction analysis with emphasis on calculations of the Flack and Hooft parameters, which are applicable to all molecules that crystallize in non-centrosymmetric space groups. The accurate molecular models of sesquiterpenes, validated by concordance with their experimental properties, are nowadays essential for the interpretation of the effects of these natural products on biological systems.

Bimolecular decomposition pathways for carboxylic acids of relevance to biofuels.

The bimolecular thermal reactions of carboxylic acids were studied using quantum mechanical molecular modeling. Previous work1 investigated the unimolecular decomposition of a variety of organic acids, including saturated, α,β-unsaturated, and β,γ-unsaturated acids, and showed that the type and position of the unsaturation resulted in unique branching ratios between dehydration and decarboxylation, [H2O]/[CO2]. In this work, the effect of bimolecular chemistry (water-acid and acid-acid) is considered with a representative of each acid class. In both cases, the strained 4-centered, unimolecular transition state, typical of most organic acids, is opened up to 6- or 8-centered bimolecular geometries. These larger structures lead to a reduction in the barrier heights (20-45%) of the thermal decomposition pathways for organic acids and an increase in the decomposition kinetics. In some cases, they even cause a shift in the branching ratio of the corresponding product slates.

From Charge State to Isosurfaces to Spectra: Unraveling the Mystery of Lys-Trp Dipeptide Fluorescence

The quest for factors controlling the partition of excitation energy between fluorescence and nonradiative processes in tryptophan is of perennial interest to spectroscopists because its fluorescence has distinct intensity, color and environmental sensitivity. Solving the relationship between specifics of molecular environment and characteristics of tryptophan fluorescence would provide the key for emission spectra interpretation of a wide variety of proteins. Our quantum mechanical calculations and molecular modeling reveal substantial differences in ground state isosurface charge distribution on the indole ring for Lys-Trp dipeptides when backbone and residue charge is varied. These isosurfaces represent the superposition of all ground state molecular orbital contributions to charge distribution and thereby provide a visual representation of the contributions of all relevant orbitals. Comparison of Lys-Trp species isosurfaces with experimentally derived quantum yields and fluorescence lifetimes reveals a correlation: high π-electron density on the indole ring is associated with high quantum yield and long average lifetime, both of which are found in the zwitterionic and anionic states. Conversely, low quantum yield and short average lifetime is associated with low, uneven π-electron density on the indole ring, which is found in the cationic and highly anionic state where the indole amine is deprotonated. This interpretation explains fluorescence results for tryptophan-containing proteins. Where x-ray crystal structures have shown proteinaceous tryptophans to be hydrogen bonded at the indole amine, very low quantum yields are observed, and isosurfaces resembling those with a deprotonated indole amine are anticipated. Thus isosurfaces reveal losses in π-electron density over the indole ring or a loss of aromaticity for low fluorescing tryptophans. Isosurfaces are the key to solving the relationship between molecular environment and tryptophan fluorescence.

Comparison of Unimolecular Decomposition Pathways for Carboxylic Acids of Relevance to Biofuels

Quantum mechanical molecular modeling is used [M06-2X/6-311++G(2df,p)] to compare activation energies and rate constants for unimolecular decomposition pathways of saturated and unsaturated carboxylic acids that are important in the production of biofuels and that are models for plant and algae-derived intermediates. Dehydration and decarboxylation reactions are considered. The barrier heights to decarboxylation and dehydration are similar in magnitude for saturated acids (∼71 kcal mol(-1)), with an approximate 1:1 [H2O]/[CO2] branching ratio over the temperature range studied (500-2000 K). α,β-Unsaturation lowers the barrier to decarboxylation between 2.2 and 12.2 kcal mol(-1) while increasing the barriers to dehydration by ∼3 kcal mol(-1). The branching ratio, as a result, is an order of magnitude smaller, [H2O]/[CO2] = 0.07. For some α,β-unsaturated acids, six-center transition states are available for dehydration, with barrier heights of ∼35.0 kcal mol(-1). The branching ratio for these acids can be as high as 370:1. β,γ-Unsaturation results in a small lowering in the barrier height to decarboxylation (∼70.0 kcal mol(-1)). β,γ-Unsaturation also leads to a lowering in the dehydration pathway from 1.7 to 5.1 kcal mol(-1). These results are discussed with respect to predicted kinetic values for acids of importance in biofuels production.

A coupled two-dimensional main chain torsional potential for protein dynamics: generation and implementation

Main chain torsions of alanine dipeptide are parameterized into coupled 2-dimensional Fourier expansions based on quantum mechanical (QM) calculations at M06 2X/aug-cc-pvtz//HF/6-31G** level. Solvation effect is considered by employing polarizable continuum model. Utilization of the M06 2X functional leads to precise potential energy surface that is comparable to or even better than MP2 level, but with much less computational demand. Parameterization of the 2D expansions is against the full main chain torsion space instead of just a few low energy conformations. This procedure is similar to that for the development of AMBER03 force field, except unique weighting factor was assigned to all the grid points. To avoid inconsistency between quantum mechanical calculations and molecular modeling, the model peptide is further optimized at molecular mechanics level with main chain dihedral angles fixed before the calculation of the conformational energy on molecular mechanical level at each grid point, during which generalized Born model is employed. Difference in solvation models at quantum mechanics and molecular mechanics levels makes this parameterization procedure less straightforward. All force field parameters other than main chain torsions are taken from existing AMBER force field. With this new main chain torsion terms, we have studied the main chain dihedral distributions of ALA dipeptide and pentapeptide in aqueous solution. The results demonstrate that 2D main chain torsion is effective in delineating the energy variation associated with rotations along main chain dihedrals. This work is an implication for the necessity of more accurate description of main chain torsions in the future development of ab initio force field and it also raises a challenge to the development of quantum mechanical methods, especially the quantum mechanical solvation models.

Hole states in Ge∕Si quantum-dot molecules produced by strain-driven self-assembly

Space-charge spectroscopy was employed to study hole emission from the confined states in vertically self-aligned double Ge quantum dots separated by a Si barrier. From the temperature- and frequency-dependent measurements, the hole binding energy was determined as a function of the separation between the dots, tSi. Increasing of the ground state hole energy due to formation of a bonding molecular orbital was found to be as large as ∼50meV at tSi=1.5nm. For a dot layer separation exceeding 3nm, the hole binding energy in double-dot molecule becomes smaller than the ionization energy of the single Ge dot, contrasting with a simplified quantum-mechanical molecular model. To analyze the experiment the electronic structure of two vertically coupled pyramidal Ge quantum dots embedded in Si was investigated by a nearest neighbor tight-binding single-particle Hamiltonian with the sp3 basis. The elastic strain due to the lattice mismatch between Ge and Si was included into the problem. The three-dimensional spatial strain distribution was found in terms of atomic positions using a valence-force-field theory with a Keating interatomic potential. It was demonstrated that formation of single-particle hole states in self-organized molecules is governed by the interplay among two effects. The first is the quantum-mechanical coupling between the individual states of two dots constituting the molecule. The second one originates from asymmetry of the strain field distribution within the top and bottom dots due to the lack of inversion symmetry with respect to the medium plane between the dots. Analysis of the biaxial strain distribution showed that anomalous decreasing of the hole binding energy below the value of the single dot with increasing interdot separation is caused by the partial strain relaxation upon dot stacking accompanied by the strain-induced reduction of the hole confinement potential. We found that the molecule-type hole state delocalized fairly over the two dots is formed only at tSi<3.3nm and at tSi>3.8nm. For the intermediate distances (3.3nm⩽tSi⩽3.8nm), the hole becomes confined mostly inside the bottom, most strained Ge dot. The overall agreement between theory and experiment turns out to be quite good, indicating the crucial role played by strain fields in electronic coupling of self-assembled quantum-dot molecules.

Hydrogen Atom Mediated Stone−Wales Rearrangement of Pyracyclene: A Model for Annealing in Fullerene Formation

We have investigated the Stone-Wales (SW) rearrangement of pyracyclene (C(14)H(12)) using quantum mechanical molecular modeling. Of particular interest in this study is the effect of an added hydrogen atom on the barriers to SW rearrangement. Hydrogen atoms are found in high abundance during combustion, and their effect upon isomerization of aromatic compounds to more stable species may play an important role in the combustion synthesis of fullerenes. We have calculated the barriers for the SW rearrangement in pyracyclene using density functional theory B3LYP/6-31G(d) and B3LYP/6-311G(d,p). Two mechanisms have been investigated: (i) a mechanism with two identical transition states of C(1) symmetry and a cyclobutyl intermediate and (ii) a mechanism with one transition state containing an sp(3) carbon (J. Am. Chem. Soc. 2003, 125, 5572-5580; Nature 1993, 366, 665-667). We find that the barriers for these mechanisms are 120.0 kcal mol(-1) for the cyclobutyl mechanism and 130.1 kcal mol(-1) for the sp(3) mechanism. Adding a hydrogen atom to the internal bridge carbon atoms of pyracyclene reduces the barrier of the cyclobutyl mechanisms to 67.0 kcal mol(-1) and the sp(3) mechanism to 73.1 kcal mol(-1). The bonding of carbon atoms in pyracyclene is similar to those found in isomers of C(60), and the barriers are low enough so that these reactions can become significant during fullerene synthesis in flames. Adding hydrogen atoms to the external bridge atoms on pyracyclene produces a smaller reduction in the SW barrier and adding hydrogen atoms to nonbridge external carbon atoms results in no reduction of the barrier.

Pharmaceutical Chemistry at the ETH Zürich

Pharmaceutical Chemistry at the ETH Zürich is devoted to research on structure–activity relationships. The combination of biophysical methods, like protein crystallography, mass spectrometry and NMR, with theoretical approaches such as QSAR studies and molecular mechanical as well as quantum mechanical molecular modeling yield insight into ligand–protein recognition and has enabled a more fundamental understanding of ligand binding and transformation in several classes of proteins. The main biological targets are and have been, kinases, major histocompatibility proteins, peptide hormones and most recently glycoproteins. In parallel the results fostered the improvement and new development of appropriate software tools for molecular design studies, the most recent of which is the automated integration of tautomeric states in docking.

ChemInform Abstract: SAM1; The First of a New Series of General Purpose Quantum Mechanical Molecular Models.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. [Erratum to document cited in CA103(2):11627f

Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. [Erratum to document cited in CA103(2):11627f

SAM1; The first of a new series of general purpose quantum mechanical molecular models

SAM1; The first of a new series of general purpose quantum mechanical molecular models

A semiempirical molecular orbital and dynamic NMR study of conformational isomerism in angiotensin-converting enzyme inhibitors

The conformational isomerism in a series of molecules related to inhibitors of the angiotensinconverting enzyme (ACE) is investigated using the semiempirical quantum mechanical molecular orbital model, AM1, and dynamic NMR spectroscopy. The theoretical method is tested by the prediction of relative barriers to rotation about amide C-N and acylhydrazine N-N bonds, and of the trans: cis ratio for a series of model compounds. The conformational energetics of captopril and a series of acylhydrazines are predicted and used to interpret the dynamic NMR spectra of these molecules, presented herein.

ChemInform Abstract: DEVELOPMENT AND USE OF QUANTUM MECHANICAL MOLECULAR MODELS. 76. AM1: A NEW GENERAL PURPOSE QUANTUM MECHANICAL MOLECULAR MODEL

Chemischer InformationsdienstVolume 16, Issue 42 Physical Organic Chemistry ChemInform Abstract: DEVELOPMENT AND USE OF QUANTUM MECHANICAL MOLECULAR MODELS. 76. AM1: A NEW GENERAL PURPOSE QUANTUM MECHANICAL MOLECULAR MODEL M. J. S. DEWAR, M. J. S. DEWARSearch for more papers by this authorE. G. ZOEBISCH, E. G. ZOEBISCHSearch for more papers by this authorE. F. HEALY, E. F. HEALYSearch for more papers by this authorJ. J. P. STEWART, J. J. P. STEWARTSearch for more papers by this author M. J. S. DEWAR, M. J. S. DEWARSearch for more papers by this authorE. G. ZOEBISCH, E. G. ZOEBISCHSearch for more papers by this authorE. F. HEALY, E. F. HEALYSearch for more papers by this authorJ. J. P. STEWART, J. J. P. STEWARTSearch for more papers by this author First published: October 22, 1985 https://doi.org/10.1002/chin.198542063AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume16, Issue42October 22, 1985 RelatedInformation

Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model

A new parametric quantum mechanical molecular model, AM1 (Austin Model l), based on the NDDO approximation, is described. In it the major weaknesses of MNDO, in particular failure to reproduce hydrogen bonds, have been overcome without any increase in computing time. Results for 167 molecules are reported. Parameters are currently available for C, H, 0, and N.

Applications of quantum mechanical molecular models to chemical problems. Part 70. Quantum mechanical molecular models

Applications of quantum mechanical molecular models to chemical problems. Part 70. Quantum mechanical molecular models

A molecular model for dielectric shifts in infrared spectra of pure liquid phases and vapor pressure isotope effects

It is demonstrated that the same red shift of infrared fundamentals in pure liquid phases which follows from a model of a molecule imbedded in a dielectric also occurs in a quantum mechanical molecular model of a system of three-dimensional isotropic harmonic oscillators. The shift arises from dipole–dipole interactions which lead to a band of excited states; transitions from the ground state are permitted only to one state in the lower part of this band. The relationship of these findings to vapor pressure isotope effects is discussed.