Computational structural determination and energy landscape analysis of the hepatic carcinogen 2-(acetylamino)fluorene

 2-(Acetylamino)fluorene (AAF), a potent mutagen and a prototypical example of the mutagenic aromatic amines, forms covalent adducts to DNA after metabolic activation in the liver. A benchmark study of AAF is presented using a number of the most widely used molecular mechanics and semiempirical computational methods and models. The results are compared to higher-level quantum calculations and to experimentally obtained crystal structures. Hydrogen bonding between AAF molecules in the crystal phase complicates the direct comparison of gas-phase theoretical calculations with experiment, so Hartree–Fock (HF) and Becke–Perdew (BP) density functional theory (DFT) calculations are used as benchmarks for the semiempirical and molecular mechanics results. Systematic conformer searches and dihedral energy landscapes were carried out for AAF using the SYBYL and MMFF94 molecular mechanics force fields; the AM1, PM3 and MNDO semiempirical quantum mechanics methods; HF using the 3-21G*and 6-31G* basis sets; and DFT using the nonlocal BP functional and double numerical polarization basis sets. MMFF94, AM1, HF and DFT calculations all predict the same planar structures, whereas SYBYL, MNDO and PM3 all predict various nonplanar geometries. The AM1 energy landscape is in substantial agreement with HF and DFT predictions; MMFF94 is qualitatively similar to HF and DFT; and the MNDO, PM3 and SYBYL results are qualitatively different from the HF and DFT results and from each other. These results are attributed to deficiencies in MNDO, PM3 and SYBYL. The MNDO, PM3 and SYBYL models may be unreliable for compounds in which an amide group is immediately adjacent to an aromatic ring. Received: 26 May 2002 / Accepted: 12 December 2002 / Published online: 14 February 2003     

Are AM1 ligand‐protein binding enthalpies good enough for use in the rational design of new drugs?

We have examined the performance of semiempirical quantum mechanical methods in solving the problem of accurately predicting protein-ligand binding energies and geometries. Firstly, AM1 and PM3 geometries and binding enthalpies between small molecules that simulate typical ligand-protein interactions were compared with high level quantum mechanical techniques that include electronic correlation (e.g., MP2 or B3LYP). Species studied include alkanes, aromatic systems, molecules including groups with hypervalent sulfur or with donor or acceptor hydrogen bonding capability, as well as ammonium or carboxylate ions. B3LYP/6-311+G(2d,p) binding energies correlated very well with the BSSE corrected MP2/6-31G(d) values. AM1 binding enthalpies also showed good correlation with MP2 values, and their systematic deviation is acceptable when enthalpies are used for the comparison of interaction energies between ligands and a target. PM3 otherwise gave erratic energy differences in comparison to the B3LYP or MP2 approaches. As one would expect, the geometries of the binding complexes showed the known limitations of the semiempirical and DFT methods. AM1 calculations were subsequently applied to a test set consisting of "real" protein active site-ligand complexes. Preliminary results indicate that AM1 could be a valuable tool for the design of new drugs using proteins as templates. This approach also has a reasonable computational cost. The ligand-protein X-ray structures were reasonably reproduced by AM1 calculations and the corresponding AM1 binding enthalpies are in agreement with the results from the "small molecules" test set.     

Semiempirical configuration interaction calculations for ru‐centered dyes*

Computational investigation of the photochemical properties of transition‐metal‐centered dyes typically involves optimization of the molecular structure followed by calculation of the UV/visible spectrum. At present, these steps are usually carried out using density functional theory (DFT) and time‐dependent DFT calculations. Recently, we demonstrated that semiempirical methods with appropriate parameterization could yield geometries that were in very good agreement with DFT calculations, allowing large sets of molecules to be screened quickly and efficiently. In this article, we modify a configuration interaction (CI) method based on a semiempirical PM6 Hamiltonian to determine the UV/visible absorption spectra of Ru‐centered complexes. Our modification to the CI method is based on a scaling of the two‐center, two‐electron Coulomb integrals. This modified, PM6‐based method shows a significantly better match to the experimental absorption spectra versus the default configuration interaction method (in MOPAC) on a training set of 13 molecules. In particular, the modified PM6 method blue‐shifts the location of the metal‐to‐ligand charge‐transfer (MLCT) peaks, in better agreement with experimental and DFT‐based computational results, correcting a significant deficiency of the unmodified method. Published 2018. This article is a U.S. Government work and is in the public domain in the USA     

Comparison of ab initio,semiempirical, and molecular mechanics calculations for the conformational analysis of ring systems

The potential energy surfaces of four cyclic alkanes have been examined using molecular mechanics, semiempirical, and ab initio methods to determine if they produce mutually consistent results and investigate the source of any errors between the methods. The C₅ ? C₈ cyclic alkanes were chosen since these structures present a finite set of conformations and transition-state geometries and are still within the computational time and memory limits of the quantum mechanical approaches. We also examined several conformations of 1,2-dideoxyribose to determine the effect of heteroatoms on the results for the 5-membered ring. The molecular mechanics and ab initio calculations are consistent in the relative energies and geometries determined for the conformers of all ring systems. While the semiempirical calculations yielded geometries consistent with the other methods (except for 5-membered rings), the relative energies often deviated substantially. A decomposition analysis of the semiempirical and molecular mechanics energies revealed that the disparities are mainly due to errors in the 1-center energies of the semiempirical calculations. The 2-center bonding and nonbonding energies followed reasonable trends for the conformers. The core-repulsion function, however, is suspected of producing anomalies. A minimum in the attractive Gaussian of this term at 2.1 Å for H? H interactions partly explains the propensity of the 5-membered rings to optimize to near planarity (decreasing 1,2-diaxial hydrogen distances to 2.3 Å) and the underestimation of the relative energy of the boat structure of cyclohexane.     

A Robust and Cost-Efficient Scheme for Accurate Conformational Energies of Organic Molecules

Several standard semiempirical methods as well as the MMFF94 force field approximation have been tested in reproducing 8 DLPNO-CCSD(T)/cc-pVTZ level conformational energies and spatial structures for 37 organic molecules representing pharmaceuticals, drugs, catalysts, synthetic precursors, industry-related chemicals (37conf8 database). All contemporary semiempirical methods surpass their standard counterparts resulting in more reliable conformational energies and spatial structures, even though at significantly higher computational costs. However, even these methods show unexpected failures in reproducing energy differences between several conformers of the crown ether 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6). Inexpensive force field MMFF94 approximation groups with contemporary semiempirical methods in reproducing the correct order of conformational energies and spatial structures, although the performance in predicting absolute conformational energies compares to standard semiempirical methods. Based on these findings, we suggest a two-step strategy for reliable yet feasible conformational search and sampling in realistic-size flexible organic molecules: i) geometry optimization/preselection of relevant conformers using the MMFF94 force field; ii) single-point energy evaluations using a contemporary semiempirical method. We expect that developed database 37conf8 is going to be useful for development of semiempirical methods.     

Structures and energies of D-galactose and galabiose conformers as calculated by ab initio and semiempirical methods

Optimized geometries and total energies of some conformers of alpha- and beta-D-galactose have been calculated using the RHF/6-31G* ab initio method. Vibrational frequencies were computed at the 6-31G* level for the conformers that favor internal hydrogen bonding, in order to evaluate their enthalpies, entropies, Gibbs free energies, and then their structural stabilities. The semiempirical AM1, PM3, MNDO methods have also been performed on the conformers GG, GT, and TG of alpha- and beta-D-galactose. In order to test the reliability of each semiempirical method, the obtained structures and energies from the AM1, PM3, and MNDO methods have been compared to those achieved using the RHF/6-31G* ab initio method. The MNDO method has not been investigated further, because of the large deviation in the structural parameters compared with those obtained by the ab initio method for the galactose. The semiempirical method that has yielded the best results is AM1, and it has been chosen to perform structural and energy calculations on the galabiose molecule (the disaccharides constituted by two galactose units alpha 1,4 linked). The goal of such calculations is to draw the energy surface maps for this disaccharide. To realize each map, 144 different possible conformations resulting from the rotations of the two torsional angles psi and phi of the glycosidic linkage are considered. In each calculation, at each increment of psi and phi, using a step of 30 degrees from 0 to 330 degrees, the energy optimization is employed. In this article, we report also calculations concerning the galabiose molecule using different ab initio levels such as RHF/6-31G*, RHF/6-31G**, and B3Lyp/6-31G*.     

Conformational study of (8alpha,8'beta)-bis(substituted phenyl)-lignano-9,9'-lactones by means of combined computational, database mining, NMR, and chemometric approaches

Beta-(3,4-Methylenedioxybenzyl)-gamma-butyrolactone (MDBL) and (-)-hinokinin (HK) were obtained by partial synthesis and characterized by 1H NMR and computational methods (conformational analysis, molecular modeling, structural data mining and chemometrics). Three conformers were detected for MDBL and nine were found for HK. The energy differences are around 1 and 2 kcal mol(-1) and rotation barriers are less than 3 and 5 kcal mol(-1) for MDBL and HK conformers, respectively. The geometries of these conformers, obtained from semiempirical PM3 and density functional theory (DFT) B3LYP 6-31G** calculations agree satisfactorily with 1H NMR data (vicinal proton-proton coupling constants) and structures retrieved from the Cambridge Structural Database (torsion angles). DFT combined with some variants of the Haasnoot-de Leeuuw-Altona equations gives the best predictions for the coupling constants. The molecular conformation of MDBL, of HK, and of related systems depends not only on intramolecular interactions but also on crystal packing forces and solvent-solute interactions, in particular hydrogen bonds and polar interactions. Hydration favors more stable HK conformers, which can be important for their behavior in chemical and biological systems.     

Testing electronic structure methods for describing intermolecular H...H interactions in supramolecular chemistry

In this article a wide variety of computational approaches (molecular mechanics force fields, semiempirical formalisms, and hybrid methods, namely ONIOM calculations) have been used to calculate the energy and geometry of the supramolecular system 2-(2'-hydroxyphenyl)-4-methyloxazole (HPMO) encapsulated in beta-cyclodextrin (beta-CD). The main objective of the present study has been to examine the performance of these computational methods when describing the short range H. H intermolecular interactions between guest (HPMO) and host (beta-CD) molecules. The analyzed molecular mechanics methods do not provide unphysical short H...H contacts, but it is obvious that their applicability to the study of supramolecular systems is rather limited. For the semiempirical methods, MNDO is found to generate more reliable geometries than AM1, PM3 and the two recently developed schemes PDDG/MNDO and PDDG/PM3. MNDO results only give one slightly short H...H distance, whereas the NDDO formalisms with modifications of the Core Repulsion Function (CRF) via Gaussians exhibit a large number of short to very short and unphysical H...H intermolecular distances. In contrast, the PM5 method, which is the successor to PM3, gives very promising results. Our ONIOM calculations indicate that the unphysical optimized geometries from PM3 are retained when this semiempirical method is used as the low level layer in a QM:QM formulation. On the other hand, ab initio methods involving good enough basis sets, at least for the high level layer in a hybrid ONIOM calculation, behave well, but they may be too expensive in practice for most supramolecular chemistry applications. Finally, the performance of the evaluated computational methods has also been tested by evaluating the energetic difference between the two most stable conformations of the host(beta-CD)-guest(HPMO) system.     

De novo prediction of ground state multiplicity and structural isomerism for transition metal complexes

Prediction of the ground state geometries and multiplicities for 33 transition metal tetrachlorides has been carried out using two different levels of quantum mechanics: semiempirical and density functional theory. All data regarding geometry and spin state provided by both computational methods were compared with experimental data when available. The calculations were performed for all possible spin multiplicities. The most important geometries for coordination number four (tetrahedral, square-planar, dodecahedral, and disphenoidal), as well as less symmetric structural isomers, were evaluated. A match between both computational methods in terms of predicted ground state multiplicity and geometry was found for 26 species, which translated into almost 80% agreement. Even though the PM3(tm) geometry prediction protocol involved more steps for isolating a feasible global minimum, the aggregate of these calculations was still orders of magnitude faster than DFT calculations using extended basis sets. The calculations indicate that caution is needed in the application of the PM3(tm) method to very high-spin transition metal complexes, but point to the suitability of very rapid semiempirical methods for reliable prediction of structural and ‘spin’ isomers, and hence their use in an efficient de novo design protocol for transition metal complexes.     

A comparison of conformational energies calculated by molecular mechanics (MM2(85), Sybyl 5.1, Sybyl 5.21, and ChemX) and semiempirical (AM1 and PM3) methods

Conformational energies of different conformers have been calculated for a series of molecules using various molecular mechanics and semiempirical methods. The quality of the force fields has also been tested by calculating barriers to rotation about carbon-carbon bonds. The molecular mechanics force fields used are MM2(85), Sybyl 5.1, Sybyl 5.21, and ChemX, ver. Jan 89. The semiempirical methods used are AM1 and PM3. Molecules with different functional groups, for which good experimental data exist, have been selected. The semiempirical methods generally calculate barriers to rotation which are lower than the experimentally determined. The conformational energies for hydrocarbons are reasonably well reproduced by all tested methods although MM2(85) gives the quantitatively best agreement with experiments. For compounds containing oxygen, nitrogen and halogens MM2(85) gives results which are in best agreement with the experimentally determined values.     

Activation Energy and Transition State Determination of the Olefin Insertion Process of Metallocene Catalysts Using a Semiempirical Molecular Orbital Calculation

The transition state of the olefin insertion process of metallocene catalysts can be determined by adopting the semiempirical PM3 model. In computational chemistry, the computational methods most employed are the ab initio method and density functional theory, which are very time consuming. The semiempirical molecular orbital method requires much less computational resources than the above methods. However, the accuracy and reliability of the semiempirical molecular orbital method remains to be determined. The PM3 model is the most recently developed the semiempirical molecular orbital method and can also be applied to transition metal calculations. This study is intended to investigate the reliability of computational results determined using semiempirical PM3 model on metallocene catalysts through comparison with published results on the density functional theory (DFT). The saddle point finding procedure is adopted to find the transition state of the ethylene insertion process of metallocene catalysts. Results on the geometry and energy trends of the ethylene insertion process of metallocene catalysts determined using the PM3 model are in good agreement with the DFT results. In addition, the saddle point of the potential energy surface of ethylene insertion is verified in accordance with the eigenvalue of the vibrational frequency spectrum. Correct eigenvalues indicate that the correct saddle point of the potential energy surface of ethylene insertion has been successfully located. Hence, the eigenvalue of the vibrational frequency spectrum is a valuable reference in terms of saddle point justification. Computational results and vibrational frequency spectrum analysis demonstrate that the PM3 model can be used to locate the correct saddle point of the potential energy surface. The results obtained using the PM3 model confirm that the eigenvalue of the transition state lies nearly on the vibrational frequency spectrum. The eigenvalues are also analyzed, providing a valuable reference for further studies of the transition state of olefin insertion of metallocene catalysts. The activation energies for the olefin insertion reaction are also studied for evaluation of the catalyst.     

Computational study on hydrolysis of cefotaxime in gas phase and in aqueous solution

We are presenting a theoretical study of the hydrolysis of a β‐lactam antibiotic in gas phase and in aqueous solution by means of hybrid quantum mechanics/molecular mechanics potentials. After exploring the potential energy surfaces at semiempirical and density functional theory (DFT) level, potentials of mean force have been computed for the reaction in solution with hybrid PM3/TIP3P calculations and corrections with the B3LYP and M06‐2X functionals. Inclusion of the full molecule of the antibiotic, Cefotaxime, in the gas phase molecular model has been demonstrated to be crucial since its carboxylate group can activate a nucleophilic water molecule. Moreover, the flexibility of the substrate implies the existence of a huge number of possible conformers, some of them implying formation of intramolecular hydrogen bond interaction that can determine the energetics of the conformers defining the different states along the reaction profile. The results show PM3 provides results that are in qualitative agreement with DFT calculations. The free energy profiles show a step‐wise mechanism that is kinetically determined by the nucleophilic attack of a water molecule activated by the proton transfer to the carboxylate group of the substrate (the first step). However, since the main role of the β‐lactamase would be reducing the free energy barrier of the first step, and keeping in mind the barrier obtained from second intermediate to products, population of this second intermediate could be significant and consequently experimentally detected in β‐lactamases, as shown in the literature. © 2012 Wiley Periodicals, Inc.     

A combined semiempirical and DFT computational protocol for studying bioorganometallic complexes: Application to molybdocene–cysteine complexes

Computational methods can help in the design of new bioorganometallic compounds. However, the presence of multihapto or σ/π metal‐ligand bonding still precludes the direct application of either pure molecular mechanics (MM) or hybrid quantum mechanics‐MM methods to study the flexibility of biomolecules in complex with organometallics. Herein, we present a computational protocol aimed to the evaluation of the relative free energies of bioorganometallic compounds, which explores the conformational space by means of Molecular Dynamics simulations using the semiempirical PM6 method coupled with the COnductor‐like Screening MOdel solvation model followed by density functional theory (DFT) calculations including the DFT‐D3 dispersion energy correction on the most stable conformers. This protocol is applied to investigate the complexes formed between cysteine and the molybdocene entity Cp₂Mo²⁺ (Cp?η⁵? C₅H₅), which has received considerable attention due to its potential antitumor activity and chemical reactivity. The calculated structures and free energies are in agreement with those of the experimentally detected molybdocene‐cysteine adducts and allow us to investigate the reaction mechanism for the formation of the most stable 1:1 and 1:2 adducts. © 2013 Wiley Periodicals, Inc.     

Conformational analysis of L-prolines in water

The results of the ring conformational analysis of L-proline, N-acetyl-L-proline, and trans-4-hydroxy-L-proline by NMR combined with calculations using density functional theory (DFT) and molecular dynamics (MD) are reported. Accurate values of 1H-1H J-couplings in water and other solvents have been determined. Using a two-site equilibrium model, the Cgamma-endo conformer of L-proline in water has been identified as intermediate between gammaTdelta [twist(Cgamma-endo, Cdelta-exo)] and gammaE [envelope(Cgamma-endo)] and the Cgamma-exo conformer as betaTgamma. Both conformers were equally populated at room temperature. The N-acetyl [cis-rotamer gammaTbeta(80%)/gammaE(20%) and trans-rotamer gammaTbeta(61%)/gammaE(39%)] and 4-hydroxy (gammaEpsilon) derivatives showed significant changes in both the population and the geometries of the preferred ring conformers. The combination of NMR predicted populations with the DFT B3LYP/6-311+G(2d,p)/IEFPCM calculations proved successful, resulting in fairly accurate predictions of J-couplings. Simulations using MD were mostly in favor of the two-site equilibrium model between Cgamma-endo and Cgamma-exo conformers, similar to that used for the analysis of NMR J-couplings. Various force fields examined for MD simulations failed to reproduce the ring conformational geometries and populations of L-proline in water accurately, while significantly better agreement with NMR was found for trans-N-acetyl-L-proline using GROMOS and AMBER force fields.     

Assessing conformer energies using electronic structure and machine learning methods

We have performed a large‐scale evaluation of current computational methods, including conventional small‐molecule force fields; semiempirical, density functional, ab initio electronic structure methods; and current machine learning (ML) techniques to evaluate relative single‐point energies. Using up to 10 local minima geometries across ~700 molecules, each optimized by B3LYP‐D3BJ with single‐point DLPNO‐CCSD(T) triple‐zeta energies, we consider over 6500 single points to compare the correlation between different methods for both relative energies and ordered rankings of minima. We find that the current ML methods have potential and recommend methods at each tier of the accuracy‐time tradeoff, particularly the recent GFN2 semiempirical method, the B97‐3c density functional approximation, and RI‐MP2 for accurate conformer energies. The ANI family of ML methods shows promise, particularly the ANI‐1ccx variant trained in part on coupled‐cluster energies. Multiple methods suggest continued improvements should be expected in both performance and accuracy.     

Conformational energetics of 1,3-dichloropropane as predicted by several calculations methods

Two semiempirical methods (MNDO and AM1), a molecular mechanics technique (MM2) and two ab initio approaches (6–31G* full optimization and 3–21G/6–31G*) were used to calculate the ordering of and energy difference between conformers in 1,3-dichloropropane. The semiempirical methods did not order the conformers properly or predict correct energy differences. Both ab initio methods ordered the conformers and predicted energy differences correctly, with the 6–31G* full optimization performing slightly better. The MM2 results were presented for calculations involving a force field with no hydrogens and a full force field of all atoms. The full force field properly ordered the conformers but did not correctly predict the energy differences. The nonhydrogen field ordered the conformers based on the Cl…Cl nonbonded distance. The data show that conformer stability is not a simple matter of maximizing the Cl…Cl nonbonded distance, but is also related to some other stabilizing interaction(s).     

Quantum chemical study of the photocoloration reaction in the napthoxazine series

Ab initio and semiempirical quantum mechanical calculations were performed to study the electronic spectra of spiroxazine photochromic compounds as well as the corresponding photoisomers. Ground-state geometries were optimized based on density functional theory (DFT). Excitation energies of the different forms were calculated using the time-dependent density functional theory (TD-DFT) method. Semiempirical calculations including configuration interactions were performed to detail the mechanism of ring opening in excited states. On the basis of the obtained potential energy profile, a complete mechanism of photocoloration able to clarify some experimental findings is provided. A correlation of the experimental quantum yield of photocoloration with the calculated properties as a function of substituent effects is proposed.     

C?H Bond dissociation of acetylene: Local density functional calculations

The C? H bond dissociation energy of acetylene was computed by both ab initio approaches and density functional theory in a local density approximation (DFT–LDA ). Structures and energies for acetylene and its dissociation products (the ethynyl and hydrogen radicals) are presented and compared. Using directly computed HCCH and HCC· energies and the exact H· value, the DFT–LDA calculations are found to yield C? H dissociation energies ranging from 129 to 131 kcal/mol, in good agreement with recent experimental and the highest level theoretical results. The DFT–LDA results show little dependence upon the computational procedure used to obtain geometries.