Molecular Conformational Energies Research Articles

A Critical Review on Engineering of d-Mannitol Crystals: Properties, Applications, and Polymorphic Control

d-mannitol is a common six-carbon sugar alcohol, which is widely used in food, chemical, pharmaceutical, and other industries. Polymorphism is defined as the ability of materials to crystallize into different crystal structures. It has been reported for a long time that d-mannitol has three polymorphs: β, δ, and α. These different polymorphs have unique physicochemical properties, thus affecting the industrial applications of d-mannitol. In this review, we firstly introduced the characteristics of different d-mannitol polymorphs, e.g., crystal structure, morphology, molecular conformational energy, stability, solubility and the analytical techniques of d-mannitol polymorphisms. Then, we described the different strategies for the preparation of d-mannitol crystals and focused on the polymorphic control of d-mannitol crystals in the products. Furthermore, the factors of the formation of different d-mannitol polymorphisms were summarized. Finally, the application of mannitol polymorphism was summarized. The purpose of this paper is to provide new ideas for a more personalized design of d-mannitol for various applications, especially as a pharmaceutical excipient. Meanwhile, the theoretical overview on polymorphic transformation of d-mannitol may shed some light on the crystal design study of other polycrystalline materials.

Small-Basis Set Density-Functional Theory Methods Corrected with Atom-Centered Potentials.

Density functional theory (DFT) is currently the most popular method for modeling noncovalent interactions and thermochemistry. The accurate calculation of noncovalent interaction energies, reaction energies, and barrier heights requires choosing an appropriate functional and, typically, a relatively large basis set. Deficiencies of the density-functional approximation and the use of a limited basis set are the leading sources of error in the calculation of noncovalent and thermochemical properties in molecular systems. In this article, we present three new DFT methods based on the BLYP, M06-2X, and CAM-B3LYP functionals in combination with the 6-31G* basis set and corrected with atom-centered potentials (ACPs). ACPs are one-electron potentials that have the same form as effective-core potentials, except they do not replace any electrons. The ACPs developed in this work are used to generate energy corrections to the underlying DFT/basis-set method such that the errors in predicted chemical properties are minimized while maintaining the low computational cost of the parent methods. ACPs were developed for the elements H, B, C, N, O, F, Si, P, S, and Cl. The ACP parameters were determined using an extensive training set of 118655 data points, mostly of complete basis set coupled-cluster level quality. The target molecular properties for the ACP-corrected methods include noncovalent interaction energies, molecular conformational energies, reaction energies, barrier heights, and bond separation energies. The ACPs were tested first on the training set and then on a validation set of 42567 additional data points. We show that the ACP-corrected methods can predict the target molecular properties with accuracy close to complete basis set wavefunction theory methods, but at a computational cost of double-ζ DFT methods. This makes the new BLYP/6-31G*-ACP, M06-2X/6-31G*-ACP, and CAM-B3LYP/6-31G*-ACP methods uniquely suited to the calculation of noncovalent, thermochemical, and kinetic properties in large molecular systems.

Fast and Accurate Quantum Mechanical Modeling of Large Molecular Systems Using Small Basis Set Hartree-Fock Methods Corrected with Atom-Centered Potentials.

There has been significant interest in developing fast and accurate quantum mechanical methods for modeling large molecular systems. In this work, by utilizing a machine learning regression technique, we have developed new low-cost quantum mechanical approaches to model large molecular systems. The developed approaches rely on using one-electron Gaussian-type functions called atom-centered potentials (ACPs) to correct for the basis set incompleteness and the lack of correlation effects in the underlying minimal or small basis set Hartree-Fock (HF) methods. In particular, ACPs are proposed for ten elements common in organic and bioorganic chemistry (H, B, C, N, O, F, Si, P, S, and Cl) and four different base methods: two minimal basis sets (MINIs and MINIX) plus a double-ζ basis set (6-31G*) in combination with dispersion-corrected HF (HF-D3/MINIs, HF-D3/MINIX, HF-D3/6-31G*) and the HF-3c method. The new ACPs are trained on a very large set (73 832 data points) of noncovalent properties (interaction and conformational energies) and validated additionally on a set of 32 048 data points. All reference data are of complete basis set coupled-cluster quality, mostly CCSD(T)/CBS. The proposed ACP-corrected methods are shown to give errors in the tenths of a kcal/mol range for noncovalent interaction energies and up to 2 kcal/mol for molecular conformational energies. More importantly, the average errors are similar in the training and validation sets, confirming the robustness and applicability of these methods outside the boundaries of the training set. In addition, the performance of the new ACP-corrected methods is similar to complete basis set density functional theory (DFT) but at a cost that is orders of magnitude lower, and the proposed ACPs can be used in any computational chemistry program that supports effective-core potentials without modification. It is also shown that ACPs improve the description of covalent and noncovalent bond geometries of the underlying methods and that the improvement brought about by the application of the ACPs is directly related to the number of atoms to which they are applied, allowing the treatment of systems containing some atoms for which ACPs are not available. Overall, the ACP-corrected methods proposed in this work constitute an alternative accurate, economical, and reliable quantum mechanical approach to describe the geometries, interaction energies, and conformational energies of systems with hundreds to thousands of atoms.

Experimental and simulation investigation of polymorphic phase transformation of N-(2-hydroxy-4-chlorobenzylidene)-4-chlor-oaniline

The polymorphic transition behavior of two forms of N-(4′-chlorosalicylidene)-4-chloroaniline, yellow form (4CC-y) and orange form (4CC-o), in solution-state and solid-state were investigated, respectively. 4CC-y can transform irreversibly to 4CC-o gradually up on heating in solid-state and its transition schema was depicted from packing styles. During recrystallization in solution, 4CC was prefer to crystallize in yellow form. Subsequently, the yellow form transformed to orange form with different speed depending on the solvents. Furthermore, the molecular conformation were analyzed with Materials Studio. Molecular conformational energy contour map with different torsion angles (namely τ1 and τ2) was prepared. The conformer and crystal parking in 4CC-y was demonstrated with lower energy, which elaborate the priority in solution crystallization.

A mechanophysical phase transition provides a dramatic example of colour polymorphism: the tribochromism of a substituted tri(methylene)tetrahydrofuran-2-one.

BackgroundDerivatives of fulgides have been shown to have interesting photochromic properties. We have synthesised a number of such derivatives and have found, in some cases, that crystals can be made to change colour on crushing, a phenomenon we have termed “tribochromism”. We have studied a number of derivatives by X-ray crystallography, to see if the colour is linked to molecular structure or crystal packing, or both, and our structural results have been supported by calculation of molecular and lattice energies.ResultsA number of 5-dicyanomethylene-4-diphenylmethylene-3-disubstitutedmethylene-tetrahydrofuran-2-one compounds have been prepared and structurally characterised. The compounds are obtained as yellow or dark red crystals, or, in one case, both. In two cases where yellow crystals were obtained, we found that crushing the crystals gave a deep red powder. Structure determinations, including those of the one compound which gave both coloured forms, depending on crystallisation conditions, showed that the yellow crystals contained molecules in which the structure comprised a folded conformation at the diphenylmethylene site, whilst the red crystals contained molecules in a twisted conformation at this site. Lattice energy and molecular conformation energies were calculated for all molecules, and showed that the conformational energy of the molecule in structure IIIa (yellow) is marginally higher, and the conformation thus less stable, than that of the molecule in structure IIIb (red). However, the van der Waals energy for crystal structure IIIa, is slightly stronger than that of structure IIIb – which may be viewed as a hint of a metastable packing preference for IIIa, overcome by the contribution of a more stabilising Coulomb energy to the overall more favourable lattice energy of structure IIIb.ConclusionsOur studies have shown that the crystal colour is correlated with one of two molecular conformations which are different in energy, but that the less stable conformation can be stabilised by its host crystal lattice.Graphical abstractGraphical representation of the structural and colour change in the tribochromic compound (III).Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-014-0070-3) contains supplementary material, which is available to authorized users.

Evaluating the Roles of Conformational Strain and Cohesive Binding in Crystalline Polymorphs of Aripiprazole

The relative stabilities of crystalline polymorphs are an important aspect of the manufacturing and effective utilization of pharmaceuticals. These stabilities are driven by both molecular conformational energy within the solid-state components and cohesive binding energy of the crystalline arrangement. The combined approach of experimental vibrational terahertz spectroscopy with solid-state density functional theory provides a powerful tool to study such properties and is applied here in the analysis of conformational polymorphism in crystalline aripiprazole. The low-frequency (<95 cm–1) terahertz vibrations of several aripiprazole polymorphs were measured, revealing distinct spectral features that uniquely identify each form. Solid-state density functional theory was employed to interpret the experimental terahertz spectra, correlating the observed spectral features to specific atomic motions within the crystalline lattice. The computational analysis provides insight into the formation and stability of ...

Conformational space exploration of met‐ and Leu‐enkephalin using the mols method, molecular dynamics, and Monte Carlo simulation—a comparative study

We report here a comparative study of the molecular conformational energy landscape generated using the mutually orthogonal Latin squares (MOLS) method, molecular dynamics (MD), and Monte Carlo (MC) simulation. The MOLS method, as described earlier from our laboratory, uses an experimental design technique to rapidly and exhaustively sample the low energy conformations of a molecule. MD and MC simulations have been used to perform similar tasks. In the comparison reported here, the three methods were applied to a pair of neuropeptides, namely Met- and Leu-enkephalin. A set of 1500 conformations of these enkephalins were generated using these methods with CHARMM22 force field, and the resulting samples were analyzed to determine the extent and nature of coverage of the conformational space. The results indicate that the MOLS method samples a larger number of possible conformations and identifies conformations closer to the experimental structures than the MD and MC simulations.

Theoretical and Predictive Modelling of Physical Properties of Polymers

The application of Boltzmann statistics to a complete distribution of molecular conformation energies of simplified homo- and copolymer models gives meaningful information about temperatures at which phase transitions take place in the bulk. We have calculated in the conformation statistical distribution (CSD) approximation Helmholtz free energy variation versus temperature δF = δU-TδS. where U and S are, respectively, the internal molecular energy and the Gibbs statistical entropy of the considered polymeric model. The deepest minima correspond to glass-transition temperature (T g ) and melting temperature (T m ) of modelled polymers, while the remaining peaks are relied to some other transitions, the existence of which is also experimentally proven. The adopted method is able to give T g and T m as a function of the molecular weight of polymers. Some indications can also be achieved about the instability of polymers. The same procedure has been applied to copolymers and blends and has given acceptable results for T g and T m as functions of the material microstructure and composition. Other thermal and mechanical properties, such as moduli, mobilities, chemical resistance to oxidation, physical tendency to miscibility, have been directly or indirectly estmated.

Dielectric relaxation and molecular conformational energy of some arylazo benzothiazine derivatives

We carry out semi-empirical calculations on some arylazo benzothiazine derivatives to obtain the energy barriers for internal rotation and dipole moments, using the PM3 Hamiltonian. By means of the correlation function method and some probabilistic procedures we describe then the dielectric relaxation of these molecules and we try to explain what the contribution of different relaxation modes is in the process of relaxation. Moreover, we account for the consequences of the nonrigidity of the molecules in dielectric response.

Stochastic molecular optimization using generalized simulated annealing

We propose a stochastic optimization technique based on a generalized simulated annealing (GSA) method for mapping minima points of molecular conformational energy surfaces. The energy maps are obtained by coupling a classical molecular force field (THOR package) with a GSA procedure. Unlike the usual molecular dynamics (MD) method, the method proposed in this study is force independent; that is, we obtain the optimized conformation without calculating the force, and only potential energy is involved. Therefore, we do not need to know the conformational energy gradient to arrive at equilibrium conformations. Its utility in molecular mechanics is illustrated by applying it to examples of simple molecules (H2O and H2O3) and to polypeptides. The results obtained for H2O and H2O3 using Tsallis thermostatistics suggest that the GSA approach is faster than the other two conventional methods (Boltzmann and Cauchy machines). The results for polypeptides show that pentalanine does not form a stable α-helix structure, probably because the number of hydrogen bonds is insufficient to maintain the helical array. On the contrary, the icoalanine molecule forms an α-helix structure. We obtain this structure simulating all Φ, Ψ pairs using only a few steps, as compared with conventional methods. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 647–657, 1998

Dielectric relaxation and molecular conformational energy of 2,4′-DPE, 3,4′-DPE, 2,3′-DPE and 3,3′-DPE (dipyridyl ethylenes)

Semi-empirical calculations were carried out on four isomers: 2,4′-, 3,4′-, 2,3′-, and 3,3′-dipyridyl ethylenes (DPE). The energy barriers for internal rotation were obtained using the PM3 Hamiltonian. The Goulon-Rivail and Williams theory were used to describe the dielectric relaxation of these molecules. It was found that steric hindrance should be taken into account for complete analyses of the dielectric responses of these molecules.

The calculations of small molecular conformation energy differences by density functional method

The differences in the conformational energies for the gauche (G) and trans(T) conformers of 1,2-difluoroethane and for myo-and scyllo-conformer of inositol have been calculated by local density functional method (LDF approximation) with geometry optimization using different sets of calculation parameters. It is shown that in the contrast to Hartree—Fock methods, density functional calculations reproduce the correct sign and value of the gauche effect for 1,2-difluoroethane and energy difference for both conformers of inositol. The results of normal vibrational analysis for1,2-difluoroethane showed that harmonic frequencies calculated in LDF approximation agree with experimental data with the accuracy typical for scaled large basis set Hartree—Fock calculations.

Application of the renormalization group to deterministic global minimization of molecular conformation energy functions

We outline a new global minimization method in which the Gibbs distribution of the objective function is deterministically annealed by tracing the evolution of a multiple-Gaussian-packet approximation. Solutions are reached by iterative approximations with decreasing coarse-graining of both objective-function and spatial scales. Results from application of a partial implementation to the atomic-microcluster conformation problem are presented.

The energy well connection graph: a use of curvilinear coordinates to achieve dimension reduction for graph representation of molecular conformation energy data

In the conformation space of a flexible molecule, curvilinear coordinate paths connecting conformations of segments of the given molecule are used to reduce the number of variables required for describing barriers between preferred conformations of the molecule as a whole. The technique is applied to a hypothetical example, then to m-trinuoromethyl-N-ethyl-amphetamine (fenfluramine), and to N-methyl-3-phenyl-3-(o-methoxyphenoxy)-propylamine (nisoxetine). In the latter example, the number of variables is thus reduced from six to three. In all three examples, a graph representation of low-energy well connection is achieved. The limit of easy comprehension has thus been moved back from about three torsion angles to three effective segments. Within this limit the procedure leads to a quantitative diagram, which is no harder to read than a contour map, showing the barriers to low-energy interconnection among the favorable conformations of a moderately complex molecule.

Moltw: A program for conformational studies using empirical functions—I. Description and general evaluation

Abstract A Fortran V (Univac) program is described which calculates molecular conformational energies on the basis of user-selected intramolecular potential energy functions. The algorithm presented here is designed to perform the computation of the conformational partition and therefore it can be used for the prediction of experimentally available quantities such as NMR chemical shifts and coupling constants. The program is efficient in the sense that only dihedral angles and pseudorotational coordinates are handled in the first steps thus allowing a rapid sampling of a great number of points through the entire conformational space. The program provides options to choose between grid searches, energy minimization or both, using a reasonable amount of computer time.