A self-organizing algorithm for molecular alignment and pharmacophore development

We present a method for simultaneous three-dimensional (3D) structure generation and pharmacophore-based alignment using a self-organizing algorithm called Stochastic Proximity Embedding (SPE). Current flexible molecular alignment methods either start from a single low-energy structure for each molecule and tweak bonds or torsion angles, or choose from multiple conformations of each molecule. Methods that generate structures and align them iteratively (e.g., genetic algorithms) are often slow. In earlier work, we used SPE to generate good-quality 3D conformations by iteratively adjusting pairwise distances between atoms based on a set of geometric rules, and showed that it samples conformational space better and runs faster than earlier programs. In this work, we run SPE on the entire ensemble of molecules to be aligned. Additional information about which atoms or groups of atoms in each molecule correspond to points in the pharmacophore can come from an automatically generated hypothesis or be specified manually. We add distance terms to SPE to bring pharmacophore points from different molecules closer in space, and also to line up normal/direction vectors associated with these points. We also permit pharmacophore points to be constrained to lie near external coordinates from a binding site. The aligned 3D molecular structures are nearly correct if the pharmacophore hypothesis is chemically feasible; postprocessing by minimization of suitable distance and energy functions further improves the structures and weeds out infeasible hypotheses. The method can be used to test 3D pharmacophores for a diverse set of active ligands, starting from only a hypothesis about corresponding atoms or groups.     

Molecular alignment in a liquid induced by a nonresonant laser field: Molecular dynamics simulation

We carried out molecular dynamics (MD) simulations for a dilute aqueous solution of pyrimidine in order to investigate the mechanisms of field-induced molecular alignment in a liquid phase. An anisotopically polarizable molecule can be aligned in a liquid phase by the interaction with a nonresonant intense laser field. We derived the effective forces induced by a nonresonant field on the basis of the concept of the average of the total potential over one optical cycle. The results of MD simulations show that a pyrimidine molecule is aligned in an aqueous solution by a linearly polarized field of light intensity I approximately 10(13) W/cm2 and wavelength lambda = 800 nm. The temporal behavior of field-induced alignment is adequately reproduced by the solution of the Fokker-Planck equation for a model system in which environmental fluctuations are represented by Gaussian white noise. From this analysis, we have revealed that the time required for alignment in a liquid phase is in the order of the reciprocals of rotational diffusion coefficients of a solute molecule. The degree of alignment is determined by the anisotropy of the polarizability of a molecule, light intensity, and temperature. We also discuss differences between the mechanisms of optical alignment in a gas phase and a liquid phase.     

Measurement and statistical analysis of single-molecule current-voltage characteristics, transition voltage spectroscopy, and tunneling barrier height

We report on the measurement and statistical study of thousands of current-voltage characteristics and transition voltage spectra (TVS) of single-molecule junctions with different contact geometries that are rapidly acquired using a new break junction method at room temperature. This capability allows one to obtain current-voltage, conductance voltage, and transition voltage histograms, thus adding a new dimension to the previous conductance histogram analysis at a fixed low-bias voltage for single molecules. This method confirms the low-bias conductance values of alkanedithiols and biphenyldithiol reported in literature. However, at high biases the current shows large nonlinearity and asymmetry, and TVS allows for the determination of a critically important parameter, the tunneling barrier height or energy level alignment between the molecule and the electrodes of single-molecule junctions. The energy level alignment is found to depend on the molecule and also on the contact geometry, revealing the role of contact geometry in both the contact resistance and energy level alignment of a molecular junction. Detailed statistical analysis further reveals that, despite the dependence of the energy level alignment on contact geometry, the variation in single-molecule conductance is primarily due to contact resistance rather than variations in the energy level alignment.     

Molecular alignment of ammonia studied by electron-ion-ion coincidence spectroscopy

Electron-ion-ion coincidence measurements carried out at discrete resonances near the N 1s threshold in ammonia are reported. The measured coincidence spectra show clear alignment of the molecule upon resonant core-electron excitation. The coincidence data are analyzed to extract information about the molecule in the excited state by simulating the alignment and the dissociation processes. Dynamic changes in molecular geometry are found as the photon energy is scanned through the N 1s-->4a(1) resonance, whereas for the N 1s-->2e state the geometry and kinetic energy released upon dissociation remain unchanged. The alignment of the core-excited molecules is found to be preserved even in two-step dissociation processes.     

Refinement of local and long-range structural order in theophylline-binding RNA using (13)C-(1)H residual dipolar couplings and restrained molecular dynamics.

13C-(1)H residual dipolar couplings (RDC) have been measured for the bases and sugars in the theophylline-binding RNA aptamer, dissolved in filamentous phage medium, and used to investigate the long-range structural and dynamic behavior of the molecule in the solution state. The orientation dependent RDC provide additional restraints to further refine the overall structure of the RNA-theophylline complex, whose long-range order was poorly defined in the NOE-based structural ensemble. Structure refinement using RDC normally assumes that molecular alignment can be characterized by a single tensor and that the molecule is essentially rigid. To address the validity of this assumption for the complex of interest, we have analyzed distinct domains of the RNA molecule separately, so that local structure and alignment tensors experienced by each region are independently determined. Alignment tensors for the stem regions of the molecule were allowed to float freely during a restrained molecular dynamics structure refinement protocol and found to converge to similar magnitudes. During the second stage of the calculation, a single alignment tensor was thus applied for the whole molecule and an average molecular conformation satisfying all experimental data was determined. Semirigid-body molecular dynamics calculations were used to reorient the refined helical regions to a relative orientation consistent with this alignment tensor, allowing determination of the global conformation of the molecule. Simultaneously, the local structure of the theophylline-binding core of the molecule was refined under the influence of this common tensor. The final ensemble has an average pairwise root mean square deviation of 1.50 +/- 0.19 A taken over all heavy atoms, compared to 3.5 +/- 1.1 A for the ensemble determined without residual dipolar coupling. This study illustrates the importance of considering both the local and long-range nature of RDC when applying these restraints to structure refinements of nucleic acids.     

Effects of polymer surface structures on liquid crystal alignment studied with molecular dynamics simulations

Effects of polymer surface structures on surface alignment of liquid crystal molecules were studied by comparison with our previous results of molecular dynamics simulations. An adsorption-related liquid crystal molecule alignment on the packed polyimide surface was found in the simulation study. In this article, we first compared the alignment on a sparse polyimide surface with the previous results of the packed polyimide surface to see effects of polymer surface density. The excluded volume effect with the polyimide domain edges additionally contributed to alignment of the liquid crystal molecules on the sparse surface, and resulted in a similar alignment structure (i.e. alignment direction and tilt angle) to the packed cases. Secondly, we made similar simulations by changing the polymer from a polyimide to a polyamide with similar polymer chain density. Differences between the corresponding packed polyimide case were found mainly in the energetics (the polyamide had about two thirds of the adsorption energy of the liquid crystal molecule as the polyimide did). The alignment structures were not so different.     

Single molecule spectroscopy of conjugated polymer chains in an electric field-aligned liquid crystal

Using single molecule polarization spectroscopy, we investigated the alignment of a polymer solute with respect to the liquid crystal (LC) director in an LC device while applying an external electric field. The polymer solute is poly[2-methoxy-5-(2'-ethyl-hexyloxy)-1,4-phenylene vinylene] (or MEH-PPV), and the LC solvent is 5CB. The electric field induces a change in the LC director orientation from a planar alignment (no electric field) to a perpendicular (homeotropic) alignment with an applied field of 5.5 x 103 V/cm. We find that the polymer chains align with the LC director in both planar and homeotropic alignment when measured in the bulk of the LC solution away from the device interface. Single molecule polarization distributions measured as a function of distance from the LC device interface reveal a continuous change of the MEH-PPV alignment from planar to homeotropic. The observed polarization distributions are modeled using a conventional elastic model that predicts the depth profile of the LC director orientation for the applied electric field. The excellent agreement between experiment and simulations shows that the alignment of MEH-PPV follows the LC director throughout the LC sample. Furthermore, our results suggest that conjugated polymers such as MEH-PPV can be used as sensitive local probes to explore complex (and unknown) structures in anisotropic media.     

In situ self-assembled photo-switchable liquid crystal alignment layer using azosilane monomer-liquid crystal mixture system

Self-assembled monolayers (SAMs) are a unique approach for the liquid crystal (LC) alignment in electro-optical applications such as displays. Herein, a new methodology for photo-switchable LC alignment layer using an azosilane monomer and LC mixture system in the absence of any other foreign alignment layer is presented. The azosilane monomer spontaneously separated from the host LCs, and formed a stable monolayer network on the substrate surface. Data from X-ray photo-electron spectroscopy (XPS), spectroscopic elipsometry (SE), water contact angle and LC alignment studies confirmed that, in the azosilane and LC mixture system, azosilane makes an in situ SAM that is capable of photo-switchable LC alignment layer on glass and indium tin oxide (ITO) substrates. The LCs are aligned with respect to change in the photo-isomerisation of the azo molecule.     

A pseudo-ligand approach to virtual screening

A virtual screening method is presented that is grounded on a receptor-derived pharmacophore model termed "virtual ligand" or "pseudo-ligand". The model represents an idealized constellation of potential ligand sites that interact with residues of the binding pocket. For rapid virtual screening of compound libraries the potential pharmacophore points of the virtual ligand are encoded as an alignment-free correlation vector, avoiding spatial alignment of pharmacophore features between the pharmacophore query (i.e., the virtual ligand) and the candidate molecule. The method was successfully applied to retrieving factor Xa inhibitors from a Ugi three-component combinatorial library, and yielded high enrichment of actives in a retrospective search for cyclooxygenase-2 (COX-2) inhibitors. The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets.     

Optimal molecular alignment and orientation through rotational ladder climbing

We study the control by electromagnetic fields of molecular alignment and orientation in a linear, rigid-rotor model. With the help of a monotonically convergent algorithm, we find that the optimal field is in the microwave part of the spectrum and acts by resonantly exciting the rotation of the molecule progressively from the ground state, i.e., by rotational ladder climbing. This mechanism is present not only when maximizing orientation or alignment, but also when using prescribed target states that simultaneously optimize the efficiency of orientation/alignment and its duration. The extension of the optimization method to consider a finite rotational temperature is also presented.     

由激光诱导荧光方法探测光碎片分子取向的理论研究

采用密度矩阵方法,推导了从激光诱导荧光(LIF)强度中抽出光碎片取向参数的表达式.光碎片的取向由分子态多极矩描述.用于解离母分子和激发碎片分子的激光均为线偏振光,而探测荧光为非偏振光.激光诱导荧光强度是光碎片分子初始态多极矩、线强度因子和解离-激发几何因子的函数.光碎片的取向参数可以由测量荧光偏振比和计算动力学因子而获得.     

Estimation of molecular similarity based on 4D-QSAR analysis: formalism and validation

The 4D-QSAR paradigm has been used to develop a formalism to estimate molecular similarity measures as a function of conformation, alignment, and atom type. It is possible to estimate the molecular similarity of pairs of molecules based upon the entire ensemble of conformational states each molecule can adopt at a given temperature, normally room temperature. Molecular similarity can be measured in terms of the types of atoms composing each molecule leading to multiple measures of molecular similarity. Multiple measures of molecular similarity can also arise from using different alignment rules to perform relative molecular similarity, RMS, analysis. An alignment independent method of determining molecular similarity measures, referred to as absolute molecular similarity, AMS, analysis has been developed. Various sets and libraries of compounds, including the amino acids, are analyzed using 4D-QSAR molecular similarity analysis to demonstrate the features of the formalism. Exploration of molecular similarity as a function of chirality, identification of common embedded 3D pharmacophores in compounds, and elucidation of 3D-isosteric compounds from structurally diverse libraries are carried out in the application studies.     

Nuclear spin selective alignment of ethylene and analogues

We investigate the alignment of ethylene and of some of its analogues via short, non-resonant laser pulses and show that it depends crucially on the nuclear spin of the molecules. We calculate the time-dependent alignment factors of the four nuclear spin isomers of ethylene and analyze them by comparison with the symmetric top molecule allene. Moreover, we explore how the nuclear spin selective alignment depends on the asymmetry of the molecules and on the intensity of the laser pulse. As an application, we discuss how nuclear spin selective alignment could be applied in order to separate different isotopomers of ethylene.     

MolAlign: an algorithm for aligning multiple small molecules

In small molecule drug discovery projects, the receptor structure is not always available. In such cases it is enormously useful to be able to align known ligands in the way they bind in the receptor. Here we shall present an algorithm for the alignment of multiple small molecule ligands. This algorithm takes pre-generated conformers as input, and proposes aligned assemblies of the ligands. The algorithm consists of two stages: the first stage is to perform alignments for each pair of ligands, the second stage makes use of the results from the first stage to build up multiple ligand alignment assemblies using a novel iterative procedure. The scoring functions are improved versions of the one mentioned in our previous work. We have compared our results with some recent publications. While an exact comparison is impossible, it is clear that our algorithm is fast and produces very competitive results.     

Novel alignment method of small molecules using the Hopfield Neural Network

Molecular alignment is an important step in three-dimensional quantitative structure-activity relationship (3D-QSAR) such as comparative molecular field analysis (CoMFA). A reasonable molecular alignment is necessary for building a 3D-QSAR model. In this paper, a novel method for molecular alignment using the Hopfield Neural Network (HNN) is introduced. Four kinds of chemical properties are assigned to each atom of a molecule. Then, those properties between two molecules correspond to each other using HNN. To validate our method, HNN was applied to 12 pairs of enzyme inhibitors cited from the Protein Data Bank (PDB). As a result, our method could successfully reproduce the real molecular alignments obtained from X-ray crystallography.     

Charge-induced spin alignment in diradical donor molecules: numerical calculations of correlated many-electron-spin systems

The mechanism of charge-induced high spin is studied in pi-conjugated molecules by means of a model-Hamiltonian approach. Intersite Coulomb interactions are taken into account in a pi-conjugated moiety, which is coupled with two localized spins through exchange interactions. We clarify spin alignment in neutral and oxidized states by exact numerical calculations including all the correlation effects. In thianthrene-based molecules, one-electron oxidation induces strong ferromagnetic correlation between the localized spins irrespective of the spin alignment in the neutral state. The localized spins are coupled to the delocalized hole spin ferromagnetically, leading to a high-spin state in the oxidized molecule. Our calculations on structural dependence and effective exchange interaction are consistent with the recent experiment of thianthrene bis(nitronyl nitroxide). By comparing the thianthrene-based molecule with the anthracene-based one, we clarify the role of superexchange interactions via the sulfur atoms.     

用双激光脉冲操纵N2分子取向

利用求解含时薛定谔方程的方法, 研究了双原子N2分子在激光强度为1.5×10¹⁴ W·cm^-2, 脉冲宽度为50 fs激光脉冲作用下的取向行为. 研究结果表明, 保持总激光强度不变, 将一束激光脉冲分成具有同样脉宽, 强度比为0.3636的两束激光脉冲, 当第一束脉冲产生的分子取向即将达到最大时, 加上有一定延迟时间的第二束脉冲能够使N2分子达到最大的取向程度.     

Determination of Complex Small‐Molecule Structures Using Molecular Alignment Simulation

Correct structural assignment of small molecules and natural products is critical for drug discovery and organic chemistry. Anisotropy‐based NMR spectroscopy is a powerful tool for the structural assignment of organic molecules, but it relies on the utilization of a medium that disrupts the isotropic motion of molecules in organic solvents. Here, we establish a quantitative correlation between the atomic structure of the alignment medium, the molecular structure of the small molecule, and molecule‐specific anisotropic NMR parameters. The quantitative correlation uses an accurate three‐dimensional molecular alignment model that predicts residual dipolar couplings of small molecules aligned by poly(γ‐benzyl‐l ‐glutamate). The technique facilitates reliable determination of the correct stereoisomer and enables unequivocal, rapid determination of complex molecular structures from extremely sparse NMR data.     

Theoretical study of determining orientation and alignment of symmetric top molecule using laser-induced fluorescence

General expressions used for extracting the orientation and alignment parameters of a symmetric top molecule from laser-induced fluorescence (LIF) intensity are derived by employing the density matrix approach. The molecular orientation and alignment are described by molecular state multipoles. Excitation and detection are circularly and linearly polarized lights, respectively. In general cases, the LIF intensity is a complex function of the initial molecular state multipoles, the dynamic factors and the excitation-detection geometrical factors. It contains a population, ten orientation and fourteen alignment multipoles. The problem of how to extract the initial molecular state multipoles from the resolved LIF intensity is discussed.