DTMM and COSMIC molecular mechanics parameters for alkylsilanes

Harmonic DTMM and COSMIC molecular mechanical force fields were extended to cover aliphatic silanes. Structures of the thirty-five molecules were examined and they generally fit approximately within experimental error. For these, root mean square deviations between the calculated and the experimentally determined geometrical data were found to be less than 0.05 Å and 1.7 deg. for bond lengths and bond angles, respectively. The accuracy of these force fields was also verified in comparison with the other force fields (MM2, MM3), semi-empirical (PM3), ab initio (HF,MP2) and density functional (B3LYP, BP86) quantum chemical methods. The relative stability of the seventeen conformations of seven simple molecules was investigated and the limitations of the DTMM software is discussed.     

Conformational analysis of thia crown ether derivatives by NMR spectroscopy and molecular mechanics calculations

Summary Addition of sulfur dichloride to tetrachlorocatechol-bisallylether (1) yields the 9- and 10-ring thia crown ether derivatives2 and3, respectively, together with the dithia-18-crown-6-ether4. The 10-membered ring compound3 represents the first thia macrocycle containing bothMarkovnikov andanti-Markovnikov constitution of the -chloro-thio structural segments in the same molecule. By¹H and¹³C NMR spectroscopy, equal amounts of two preferred conformers of the only isolated diastereomer of3 were observed at temperatures below –50°C. The signals were assigned to these conformers using COSY, HETCOR, and phase sensitive NOESY spectra at low temperatures. The preferred conformations and the relative configuration were determined using the different effects of _gauche -and _anti -positions in¹³C NMR chemical shifts and analyzing vicinal³ J _H,H coupling constants. These results were confirmed by molecular mechanics calculations.Dedicated to Prof. Dr.Rolf Borsdorf on the occasion of his 65^th birthday     

On the suitability of semiempirical calculations as sources of force field parameters

Summary The suitability of Dewar's Hamiltonians as a source of bonded force field parameters is explored from the comparison analysis between up to 270 semiempirically derived force field parameters and experimentally derived values reported in some of the most popular force fields. From the statistical analysis of the results, some general conclusions about the semiempirical parametrization are formulated.     

Conformational sensitivity of polyether macrocycles to electrostatic potential: Partial atomic charges,molecular mechanics,and conformational prediction

Molecular recognition (whether by enzymes, the immune system, or chelating ligands) depends critically on molecular conformation. Molecular mechanics predicts energetically favorable molecular conformations by locating low energy conformations using an empirical fit of molecular potential energy as a function of internal coordinates. Molecular mechanics analysis of 18-crown-6 demonstrates that the nonbonded term (primarily the electrostatic part) is the largest contributor to the conformational energy. Nevertheless, common methods of treating the electrostatic interaction for 18-crown-6 yield inconsistent values for conformational energies partly because partial charges assigned to each atom can change with conformation due to through-space inductive effects which are not considered in most molecular mechanics programs. Similar findings from several other groups are reviewed to support our conclusions. We argue for care and caution in predicting conformational preferences of molecules with two or more highly polar atoms. We also discuss the desirability of using an empirical method of partial charge determination such as the charge equilibration algorithm of Rappé and Goddard (or a suitable generalization which includes polarization) as a method of including these effects in molecular mechanics and molecular dynamics calculations.     

A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations

Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of epsilon = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed.     

Extended electron distributions applied to the molecular mechanics of some intermolecular interactions

Summary Extended electron distributions (XEDs) have been added to the molecular mechanics Coulombic term and applied to a selection of intermolecular interactions. The results from this approach have been compared with the commonly used atom-centred charges and more rigorous AM1-derived natural atom orbital point densities. The use of XEDs generally improves the simulation of experimental and ab initio results over the other two charge allocations and corrects geometries in those cases for which the others yield wrong results.     

The inclusion of electrostatic hydration energies in molecular mechanics calculations

Summary The problem of including solvent effects in molecular mechanics calculations is discussed. It is argued that the neglect of charge-solvent (solvation) interactions can introduce significant errors. The finite difference Poisson-Boltzmann (FDPB) method for calculating electrostatic interactions is summarized and is used as a basis for introducing a new pairwise energy term which accounts for charge-solvent interactions. This term acts between all pairs of atoms usually considered in molecular mechanics calculations and can be easily incorporated into existing force fields. As an example, a parameterization is developed for the CHARMm force field and the results compared to the predictions of the FDPB method. An approach to the realistic incorporation of solvent screening into force fields is also outlined.     

Determination of a set of parameters for the molecular modelling of phosphorothioate DNA

Phosphorothioate DNAs, have emerged as a new class of potent drugs. They are obtained by the replacement of the anionic oxygens of the phophodiester backbone by sulphur. A set of parameters has been developed for the FLEX force field implemented in JUMNA 10.0 to take into account the influence of sulphur on the structure of the DNA double helix. The consistency of our parameters was tested by modelling a phosphorothioate oligomer namely d(GC)8. d(GC)8. Results, obtained on both R-p_S and S-p_S diastereoisomers, were compared to the phosphodiester counterpart and are in agreement with available experimental data. Thus, our set of parameters seems suitable for further molecular modelling of other phosphorothioate oligomers. Received: 15 July 1998 / Accepted: 8 September 1998 / Published online: 10 December 1998     

Pattern recognition in molecular quantum mechanics

It is shown that the classical concept of an open system does not encompass quantal systems but has to be replaced by the non-Boolean notion of an entangled system. Molecular, chemical, or biological phenomena can be considered to be reduced to a fundamental theory like quantum mechanics only if the fundamental and the phenomenological theories are formally and interpretatively connected, and if the classifications used in the empirical sciences are shown to follow from a single set of fundamental dynamical laws. These conditions enforce a non-statistical and ontic interpretation of quantum mechanics, hence a non-Boolean calculus of propositions. In this interpretation the notion of a world state is well-defined, its Schmidt-decomposition defines a background-dependent model state for molecular systems and creates the phenomena we can observe. To any molecular system there is associated in an objective way a nonnegative number which we call the integrity. The integrity measures the inherent fuzziness of the system concept in a holistic theory, and is used to define recognizable molecular patterns.     

Fractal phenomena in molecular mechanics calculation

It is proposed that in molecular mechanics calculation points belonging to various stable or meta-sta-ble conformtrs are mixed up and form fractal structures in conformation space.The calculation results show the following two phenomena:(i)Two levels of structure with fractal feature were observed.Around the conformer without mirror symmetry points belonging to the conformer and its enantiomer are mixed up and form the first level of fractal structure; on the boundary of the attractive basin o{ each atlractor,points belonging to different attractors form the second level of fractal structure.(ii) The variation of molecular mechanics parameters will influence the structure and area of each attractive basin significantly The above phenomena may become the basis of a new method for solving the troublesome multi-minimum-point problem in molecular mechanics calculation.     

Extended electron distributions applied to the molecular mechanics of some intermolecular interactions. II. Organic complexes

Summary Extended electron distributions (XEDs) have been used to simulate the formation of complexes by intermolecular interaction via: (i) aromatic stacking; and (ii) hydrogen bonding. The results qualitatively reproduce experimental observations. In contrast, atom-centred partial charges fail to reproduce highly hydrogen-bonded systems, but make little difference in cases where interactions are driven largely by van der Waals forces. The dielectric constant used in the Coulombic term has been shown to be significant in defining the type and properties of these interactions when XEDs are employed. Some consideration has been given to solvation and entropy effects.     

Charge calculations in molecular mechanics. IX. A general parameterisation of the scheme for saturated halogen,oxygen and nitrogen compounds

Summary The CHARGE2 program for the calculation of partial atomic charges has been amended to include bond parameters for a number of organic functional groups, including halogens, nitrogen and oxygen. These minor amendments to the original scheme produce dipole moments for the fluoro and chloro compounds which are in complete agreement with the observed values.The less complete data sets for the bromo and iodo compounds are also well reproduced, and the dipole moments of a variety of mixed halo compounds are now in better agreement with experiment than previously.The calculated dipole moments of the saturated nitrogen and oxygen compounds are now in much better agreement than in the original scheme, thus the revised parameterisation may be employed with confidence to predict the electrostatic energies of these compounds.Furthermore, the revised scheme now gives a precise proportionality between the charge on the proton in a CH group and the ¹H chemical shift of the corresponding proton, allowing the general prediction, in principle, of ¹H chemical shifts. In addition, attempts to include variable electronegativity in the effect are described for fluoro compounds.For part VIII see Ref. 1.     

Charge calculations in molecular mechanics. III: Amino acids and peptides

Atomic charges obtained with a previously published charge scheme are given for amino acids and peptides. In order to do this, a method of handling charged species with the basic scheme^2,3 has been developed. The charges obtained for alkylammonium ions and carboxylate ions with the scheme are presented and compared with CNDO and ab initio values. The calculated experimental dipole moments of the zwitterionic forms of glycine, alanine and β-alanine are then discussed. Finally, the atomic charges obtained for the naturally occurring amino acids are given, both in the form of the N-acetyl-N′-methyl amino acid amides, used as models for the amino acid residues in enzymes, and as the free zwitterionic amino acids. The charges obtained show a good correlation with n. m. r. chemical shifts of both carbon and hydrogen atoms.     

A computationally efficient alternative to the Buckingham potential for molecular mechanics calculations

This paper describes a (6-8) variant of the Lennard-Jones (6-12) potential,for computing the energy of non-bonded interactions in molecular mechanicscalculations, which combines the overall precision of the Buckingham (6-exp)potential with the computational efficiency of the standard Lennard-Jones(6-12) potential. There is also a note on the radius of convergence of thefull matrix Newton–Raphson optimization procedure.     

ANLIZE: A molecular mechanics force field visualization tool and its application to 18-crown-6

We describe a software tool that allows one to visualize and analyze the importance of each individual steric interaction in a molecular mechanics force field. ANLIZE is presently implemented for the Dreiding force field for use with the Cerius2 software package, but could be implemented in any molecular mechanics package with a graphical user interface. ANLIZE calculates individual interactions in the force field, sorts them by size, and displays them in several ways from a menu of choices. This allows the user to scan through selected interactions to visualize which interactions are the primary determinants of preferred conformations. The features of ANLIZE are illustrated using 18-crown-6 as an example, and the factors governing conformational preference in 18-crown-6 are demonstrated. Users of molecular mechanics packages are encouraged to demand this functionality from commercial software producers.     

Model building and molecular mechanics calculations of mitoxantrone-deoxytetranucleotide complexes: Molecular foundations of DNA intercalation as cytostatic active principle

Summary Several intercalation complexes of the antitumor-active drug mitoxantrone with base paired tetranucleotides were constructed by molecular modeling using computer graphics and molecular mechanics calculations. The mitoxantrone molecule favours DNA binding into CG intercalation site. The two side chains of the drug are orientated into the major groove and fixed by hydrogen bonds with the nucleotide bases. This molecular study can be helpful for understanding the mode of action of cytostatically active compounds and to design new structurally related compounds of the anthraquinone drug type.Dedicated to Prof. Dr. Dr. h.c. mult.H. Oelschläger on the occasion of his 75^th birthday     

Ferroelectric Polarization Modulated Facet-selective Charge Separation in Bi4NbO8Cl Single Crystal for Boosting Visible-light Driven Bifunctional Water Splitting

Developing bifunctional water-splitting photocatalysts is meaningful, but challenged by the harsh requirements of specific-facet single crystals with spatially separated reactive sites and anisotropic charge transfer paths contributed by well-built charge driving force. Herein, tunable ferroelectric polarization is introduced in Bi₄NbO₈Cl single crystal nanosheets to strengthen the orthogonal charge transfer channels. By manipulating the in-plane polarization from octahedral off-centering of Nb⁵⁺ and out-of-plane polarization from lone pair electron effect of anisotropic Bi³⁺, both the fast charge recombination in bulk catalyst and the process of charge trapping into surface states can be effectively modulated. Collaborating with modest polarization electric field and facet junction induced built-in electric field, cooperative charge tractive force is constructed, which reinforces the spatial separation and migration of photogenerated electrons and holes to {110} reductive site facet and {001} oxidation site facet, respectively. While excessive polarization charges impair the facet-selective charge separation characteristics and conversely promote charge recombination on the surface. As a result, polarity-optimized Bi₄NbO₈Cl shows an excellent H₂ and O₂ evolution rate of 54.21 and 36.08 μmol ⋅ h⁻¹ in the presence of sacrificial reagents under visible light irradiation. This work unveils the function of ferroelectric polarization in tuning the intrinsic facet-selective charge transfer process of photocatalysts.     

Stereochemistry of ulapualides,a new family of tris-oxazole-containing macrolide ionophores from marine nudibranchs. A molecular mechanics study

Summary A molecular mechanics study of the marine metabolite ulapualide A, which is suggested to have ionophorie properties, has been carried out on various metal chelated complexes in order to predict the stereochemistry of the natural product. The results suggest a stereochemistry for ulapualide A which is closely similar to structurally related marine metabolites, whose stereochemistries have been established by X-ray crystallography and by partial synthesis.     

Molecular Mechanics Calculations in Organic Chemistry: Examples of the Usefulness of this Simple Non-Quantum Mechanical Model

Various problems arising in experimental organic chemistry can be clarified by molecular mechanics or force field calculations: molecular dynamics (conformational analysis and internal rotation), the search for the most stable isomer of various polycyclic hydrocarbons, reactivity calculations, including solvolysis of bridgehead substituted systems. Such calculations are shown to be useful in elucidating the mechanism of multistep carbonium ion rearrangement, for predicting the structure and stability of anti-Bredt olefins, and also offer an explanation for the selectivity observed in the hydrogenolysis of strained polycyclic smallring hydrocarbons, for the identification of long bonds and electronic effects, for the analysis of late transition states, and for the product distribution in complex reactions.     

COSMIC(90): An improved molecular mechanics treatment of hydrocarbons and conjugated systems

Summary Four modifications to the COSMIC molecular mechanics force field are described, which greatly increase both its versatility and the accuracy of calculated conformational energies. The Hill non-bonded van der Waals potential function has been replaced by a two-parameter Morse curve and a new H-H potential, similar to that in MM3, incorporated. Hydrocarbon energies in particular are much improved.A simple iterative Hückel pi-electron molecular orbital calculation allows modelling of conjugated systems. Calculated bond lengths and rotational barriers for a series of conjugated hydrocarbons and nitrogen heterocycles are shown to be as accurate as those determined by the MM2 SCF method.Explicit hydrogen-bonding potentials for H-bond acceptor-donor atom pairs have been included to give better hydrogen bond energies and lengths. The van der Waals radii of protonic hydrogens are reduced to 0.5 Å and the energy well depth is increased to 1.0 kcal mol^-1.Two new general atom types, N⁺ _sp ² and O^- _sp ³ , have been introduced which allow a wide variety of charged conjugated systems to be studied. A minimum of parameterisation is required, as the new types are easily included in the Hückel scheme which automatically adjusts bond and torsional parameters according to the defined bond-order relationships.