Molecular positional order in a dipalmitoylphosphatidic acid Langmuir–Blodgett monolayer by atomic force microscopy

Langmuir–Blodgett monolayers of dipalmitoylphosphatidic acid were studied by using atomic force microscopy on the large- and nano-scale. A molecularly resolved image was achieved at high surface pressure. The monolayer shows a dramatic long-range orientational and positional ordering of molecular organization of aliphatic tails. The ordered molecular arrangement of aliphatic tails may result from the strong intermolecular hydrogen bonding interactions between adjacent phosphate groups in the polar region.     

用原子力显微镜研究磷脂酸Langmuir-Blodgett双层膜中超分子结构

用原子力显微镜研究了二棕榈酰磷脂酸(DPPA)双层LB膜的分子排列结构,发现DPPA双层膜的分子排列具有长程的位置和取向有序,为有序六方结构;同时,在DPPA双层膜的极性区磷酸基团间存在局域超分子结构.     

Hydrophobic hydration in an orientational lattice model

To shed light on the microscopic mechanism of hydrophobic hydration, we study a simplified lattice model for water solutions in which the orientational nature of hydrogen bonding as well as the degeneracy related to proton distribution are taken into account. Miscibility properties of the model are looked at for both polar (hydrogen bonding) and nonpolar (non-hydrogen bonding) solutes. A quasichemical solution for the pure system is reviewed and extended to include the different kinds of solute. A Monte Carlo study of our model yields a novel feature for the local structure of the hydration layer: energy correlation relaxation times for solvation water are larger than the corresponding relaxation times for bulk water. This result suggests the presence of ordering of water particles in the first hydration shell. A nonassociating model solvent, represented by a lattice gas, presents opposite behavior, indicating that this effect is a result of the directionality of the interaction. In presence of polar solutes, we find an ordered mixed pseudophase at low temperatures, indicating the possibility of closed loops of immiscibility.     

Computational combinatorial ligand design: Application to human α-thrombin

Summary A new method is presented for computer-aided ligand design by combinatorial selection of fragments that bind favorably to a macromolecular target of known three-dimensional structure. Firstly, the multiple-copy simultaneous-search procedure (MCSS) is used to exhaustively search for optimal positions and orientations of functional groups on the surface of the macromolecule (enzyme or receptor fragment). The MCSS minima are then sorted according to an approximated binding free energy, whose solvation component is expressed as a sum of separate electrostatic and nonpolar contributions. The electrostatic solvation energy is calculated by the numerical solution of the linearized Poisson-Boltzmann equation, while the nonpolar contribution to the binding free energy is assumed to be proportional to the loss in solvent-accessible surface area. The program developed for computational combinatorial ligand design (CCLD) allows the fast and automatic generation of a multitude of highly diverse compounds, by connecting in a combinatorial fashion the functional groups in their minimized positions. The fragments are linked as two atoms may be either fused, or connected by a covalent bond or a small linker unit. To avoid the combinatorial explosion problem, pruning of the growing ligand is performed according to the average value of the approximated binding free energy of its fragments. The method is illustrated here by constructing candidate ligands for the active site of human -thrombin. The MCSS minima with favorable binding free energy reproduce the interaction patterns of known inhibitors. Starting from these fragments, CCLD generates a set of compounds that are closely related to high-affinity thrombin inhibitors. In addition, putative ligands with novel binding motifs are suggested. Probable implications of the MCSS-CCLD approach for the evolving scenario of drug discovery are discussed.     

Computational identification of epitopes in the glycoproteins of novel bunyavirus (SFTS virus) recognized by a human monoclonal antibody (MAb 4-5)

In this work, we have developed a new approach to predict the epitopes of antigens that are recognized by a specific antibody. Our method is based on the “multiple copy simultaneous search” (MCSS) approach which identifies optimal locations of small chemical functional groups on the surfaces of the antibody, and identifying sequence patterns of peptides that can bind to the surface of the antibody. The identified sequence patterns are then used to search the amino-acid sequence of the antigen protein. The approach was validated by reproducing the binding epitope of HIV gp120 envelop glycoprotein for the human neutralizing antibody as revealed in the available crystal structure. Our method was then applied to predict the epitopes of two glycoproteins of a newly discovered bunyavirus recognized by an antibody named MAb 4-5. These predicted epitopes can be verified by experimental methods. We also discuss the involvement of different amino acids in the antigen–antibody recognition based on the distributions of MCSS minima of different functional groups.     

Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach

Inhibition of dimerization to the active form of the HIV-1 aspartic proteinase (HIV-1 PR) may be a way to decrease the probability of escape mutations for this viral protein. The Multiple Copy Simultaneous Search (MCSS) methodology was used to generate functionality maps for the dimerization interface of HIV-1 PR. The positions of the MCSS minima of 19 organic fragments, once postprocessed to take into account solvation effects, are in good agreement with experimental data on peptides that bind to the interface. The MCSS minima combined with an approach for computational combinatorial ligand design yielded a set of modified HIV-1 PR C-terminal peptides that are similar to known nanomolar inhibitors of HIV-1 PR dimerization. A number of N-substituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR.     

Humidity-dependent dynamic infrared linear dichroism study of a poly(ester urethane)

Fourier transform infrared techniques, infrared difference spectroscopy and dynamic infrared linear dichroism (DIRLD), have been utilized to explore the effects of humidity and water absorption on a poly(ester urethane). An environmental infrared microbalance cell was used to measure the infrared spectra as a function of humidity and accompanying weight change for the absorption-desorption processes. The infrared difference data indicate that exposure to humidity affects the hydrogen-bonding interactions in the polymer. Dynamic infrared linear dichroism studies in tensile deformation mode as a function of humidity demonstrate how changes in water content affect the orientational response of functional groups. Complex behavior as a function of humidity for functional groups involved in hydrogen bonding indicates that water absorbed by the polymer affects the micro-environments near these functional groups.     

Ultrafast hydrogen bond strengthening of the photoexcited fluorenone in alcohols for facilitating the fluorescence quenching

The time-dependent density functional theory (TDDFT) method was performed to investigate the excited-state hydrogen-bonding dynamics of fluorenone (FN) in hydrogen donating methanol (MeOH) solvent. The infrared spectra of the hydrogen-bonded FN-MeOH complex in both the ground state and the electronically excited states are calculated using the TDDFT method, since the ultrafast hydrogen-bonding dynamics can be investigated by monitoring the vibrational absorption spectra of some hydrogen-bonded groups in different electronic states. We demonstrated that the intermolecular hydrogen bond C=O...H-O between fluorenone and methanol molecules is significantly strengthened in the electronically excited-state upon photoexcitation of the hydrogen-bonded FM-MeOH complex. The hydrogen bond strengthening in electronically excited states can be used to explain well all the spectral features of fluorenone chromophore in alcoholic solvents. Furthermore, the radiationless deactivation via internal conversion (IC) can be facilitated by the hydrogen bond strengthening in the excited state. At the same time, quantum yields of the excited-state deactivation via fluorescence are correspondingly decreased. Therefore, the total fluorescence of fluorenone in polar protic solvents can be drastically quenched by hydrogen bonding.     

Side group functionalized liquid crystalline polymers and blends VII. Phase behaviour and elastic constants K1 and K3 for hydrogen bonded blends of a functionalized LC copolymer with a low molecular mass non-mesogenic dopant

New hydrogen bonded blends of LC copolymers containing functional carboxyl groups with a low molecular mass pyridine-containing dopant were obtained and the orientational, optical and elastic properties of the blends were measured using the Fréedericksz method of threshold transitions in a magnetic field. The averaged order parameter S of the hydrogen bonded blends is found to be lower than that of the initial functionalized LC polymers. Furthermore, a considerable increase in the K₃/K₁ ratio is observed caused by an increment in the average 'effective' length of the hydrogen bonded mesogenic group. For the first time it is proven that LC blends with hydrogen bonded mesogenic groups obey the same main relationship of orientational elastic deformations as common nematic LC polymers with covalent bonding of mesogenic side groups.     

Use of MCSS to design small targeted libraries: application to picornavirus ligands.

Computational methods were used to design structure-based combinatorial libraries of antipicornaviral capsid-binding ligands. The multiple copy simultaneous search (MCSS) program was employed to calculate functionality maps for many diverse functional groups for both the poliovirus and rhinovirus capsid structures in the region of the known drug binding pocket. Based on the results of the MCSS calculations, small combinatorial libraries consisting of 10s or 100s of three-monomer compounds were designed and synthesized. Ligand binding was demonstrated by a noncell-based mass spectrometric assay, a functional immuno-precipitation assay, and crystallographic analysis of the complexes of the virus with two of the candidate ligands. The P1/Mahoney poliovirus strain was used in the experimental studies. A comparison showed that the MCSS calculations had correctly identified the observed binding site for all three monomer units in one ligand and for two out of three in the other ligand. The correct central monomer position in the second ligand was reproduced in calculations in which the several key residues lining the pocket were allowed to move. This study validates the computational methodology. It also illustrates that subtle changes in protein structure can lead to differences in docking results and points to the importance of including target flexibility, as well as ligand flexibility, in the design process.     

Amide I vibrational dynamics of N-methylacetamide in polar solvents: the role of electrostatic interactions

The vibrational frequency of the amide I transition of peptides is known to be sensitive to the strength of its hydrogen bonding interactions. In an effort to account for interactions with hydrogen bonding solvents in terms of electrostatics, we study the vibrational dynamics of the amide I coordinate of N-methylacetamide in prototypical polar solvents: D2O, CDCl3, and DMSO-d6. These three solvents have varying hydrogen bonding strengths, and provide three distinct solvent environments for the amide group. The frequency-frequency correlation function, the orientational correlation function, and the vibrational relaxation rate of the amide I vibration in each solvent are retrieved by using three-pulse vibrational photon echoes, two-dimensional infrared spectroscopy, and pump-probe spectroscopy. Direct comparisons are made to molecular dynamics simulations. We find good quantitative agreement between the experimentally retrieved and simulated correlation functions over all time scales when the solute-solvent interactions are determined from the electrostatic potential between the solvent and the atomic sites of the amide group.     

Impact of Positional Isomerism on Pathway Complexity in Aqueous Media

Pathway complexity has become an important topic in recent years due to its relevance in the optimization of molecular assembly processes, which typically require precise sample preparation protocols. Alternatively, competing aggregation pathways can be controlled by molecular design, which primarily rely on geometrical changes of the building blocks. However, understanding how to control pathway complexity by molecular design remains elusive and new approaches are needed. Herein, we exploit positional isomerism as a new molecular design strategy for pathway control in aqueous self‐assembly. We compare the self‐assembly of two carboxyl‐functionalized amphiphilic BODIPY dyes that solely differ in the relative position of functional groups. Placement of the carboxyl group at the 2‐position enables efficient pairwise H‐bonding interactions into a single thermodynamic species, whereas meso‐substitution induces pathway complexity due to competing hydrophobic and hydrogen bonding interactions. Our results show the importance of positional engineering for pathway control in aqueous self‐assembly.     

Theoretical study of salicylaldehyde conformal isomers and their intramolecular oxygen and hydrogen relations

To verify the semiempirical‐type localized hydrogen bonding analysis methods introduced by us several years ago, the intramolecular oxygen and hydrogen relations within salicylaldehyde are selected as the major topic in this theoretical study. The B3LYP/6‐31G** density functional method is chosen for both the full‐optimization and frequency‐type calculations. Four ortho‐type planar conformal isomers are proven to be local minima, and four internal rotation transition states are found by QST3‐type calculation. The special interpretations of  CHO and  OH characteristic frequencies, energy barriers, and thermal chemical results are discussed. In the semiempirical scheme, both local hydrogen bonding population analysis and localized hydrogen bond energy breaking procedures are applied to five pairs of related oxygen and hydrogen atoms in each isomer. The explanations for the strong or weak hydrogen bonds and intra‐CHO repulsion relationships are discussed. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 74: 395–404, 1999     

A threaded loop conformation adopted by a family of peptoid nonamers

Non-natural polymers with well-defined three-dimensional folds offer considerable potential for engineering novel functions that are outside the scope of biological polymers. Here we describe a family of N-substituted glycine or "peptoid" nonamers that folds into an unusual "threaded loop" structure of exceptional thermal stability and conformational homogeneity in acetonitrile. The structure is chain-length-specific and relies on bulky, chiral side chains and chain-terminating functional groups for stability. Notable elements of the structure include the engagement of the positively charged amino terminus by carbonyl groups of the backbone through hydrogen bonding interactions and shielding of polar groups from and near-complete exposure of hydrophobic groups to solvent, in a manner resembling a folded polypeptide globular domain turned inside-out. The structure is stable in a variety of organic solvents but is readily denatured in any solvent/cosolvent milieu with hydrogen bonding potential. The structure could serve as a scaffold for the elaboration of novel functions and could be used to test methodologies for predicting solvent-dependent polymer folding.     

Studies of the influence of hydrogen chloride on the liquid chromatographic properties of amino bonded phases

Summary The influence of hydrogen chloride on the retention properties of aminopropyl bonded phases is studied using a series of simple aromatics, phenols and acids. The result of the HCL treatment is to mediate the hydrogen bonding interaction between the solute's polar functional groups and the bound amino groups.     

Mimicking the Structure and Function of DNA: Insights into DNA Stability and Replication

The physical and chemical factors that allow DNA to perform its functions in the cell have been studied for several decades. Recent advances in the synthesis and manipulation of DNA have allowed this field to move ahead especially rapidly during the past fifteen years. One of the most common chemical approaches to the study of interactions involving DNA has been the use of DNA base analogues in which functional groups are added, deleted, blocked, or rearranged. Here we describe a different strategy, in which the polar natural DNA bases are replaced by nonpolar aromatic molecules of the same size and shape. This allows the evaluation of polar interactions (such as hydrogen bonding) with little or no interference from steric effects. We have used these nonpolar nucleoside isosteres as probes of noncovalent interactions such as DNA base pairing and protein - DNA recognition. We have found that, while base-pairing selectivity does depend on Watson - Crick hydrogen bonding in the natural pairs, it is possible to design new bases that pair selectively and stably in the absence of hydrogen bonds. In addition, studies have been carried out with DNA polymerase enzymes to investigate the importance of Watson - Crick hydrogen bonding in enzymatic DNA replication. Surprisingly, this hydrogen bonding is not necessary for efficient enzymatic synthesis of a base pair, and significant levels of selectivity can arise from steric effects alone. These results may have significant impact both on the study of basic biomolecular interactions and in the design of new, functionally active biomolecules.     

Development of three end-capped para-benzoyl calix[4,6, or 8]arene bonded stationary phases for HPLC

Three end-capped para-benzoyl calixarene bonded silica gel stationary phases are prepared and characterized by elemental analysis, infrared spectroscopy, and thermal analysis. The comparison and selectivity of these phases are investigated by using PAHs, disubstituted benezene, and naphthalene positional isomers as probes. Possible separation mechanism based on the different interactions between calixarenes and analytes are discussed. The results indicate that the separation for those analytes are influenced by the supramolecular interaction including π-π interaction, π-electron transfer interactions, space steric hindrance, and hydrogen bonding interaction on the calixarene columns. Importantly, the aromatic probes with polar groups such as -OH, -NO(2), and -NH(2) could regulate the selectivity of calixarene-bonded stationary phases.     

Oxime decorated cavitands functionalized through solvent-assisted grinding

In order to assemble supramolecular capsules, there is a need for reliable and effective synthetic methods for decorating cavitand-based host structures with appropriate functional groups. The synthesis of four different cavitands of significantly different depth and interior volume functionalized with four aldoxime groups capable of forming homomeric or heteromeric capsules through hydrogen bonding is reported. The final step in each synthesis, the aldehyde to oxime transformation, has been achieved in excellent yields through 'solvent assisted grinding'.     

Carbonyl groups as molecular valves to regulate chloride binding to squaramides

Environment-sensitive binding of anions to synthetic receptors is important for the functional mimicry of ion channels. We describe new squaramide-based chloride ion receptors whose anion binding cavity can be opened and closed by using carbonyl groups as valves. In nonpolar solvents, the carbonyls preclude chloride binding via intramolecular hydrogen bonding with the squaramide NHs. In polar solvents, disruption of the intramolecular hydrogen bonds reorients the carbonyl groups and opens the anion-binding cavity.