Molecular Tweezers: Concepts and Applications

Taken to the molecular level, the concept of “tweezers” opens a rich and fascinating field at the convergence of molecular recognition, biomimetic chemistry and nanomachines. Composed of a spacer bridging two interaction sites, the behaviour of molecular tweezers is strongly influenced by the flexibility of their spacer. Operating through an “induced‐fit” recognition mechanism, flexible molecular tweezers select the conformation(s) most appropriate for substrate binding. Their adaptability allows them to be used in a variety of binding modes and they have found applications in chirality signalling. Rigid spacers, on the contrary, display a limited number of binding states, which lead to selective and strong substrate binding following a “lock and key” model. Exquisite selectivity may be expressed with substrates as varied as C₆₀, nanotubes and natural cofactors, and applications to molecular electronics and enzyme inhibition are emerging. At the crossroad between flexible and rigid spacers, stimulus‐responsive molecular tweezers controlled by ionic, redox or light triggers belong to the realm of molecular machines, and, applied to molecular tweezing, open doors to the selective binding, transport and release of their cargo. Applications to controlled drug delivery are already appearing. The past 30 years have seen the birth of molecular tweezers; the next many years to come will surely see them blooming in exciting applications.     

平面环辛四烯:分子结构操纵实例

环辛四烯为一不平面分子,一般相信,理论中的平面环辛四烯需要将一对不成对电子填入两个简并不成键轨道,因而引起之伪扬-泰勒效应,可使带 D_(8h)对称性之平面环辛四烯非平面化而成“船”形的结构。本文简单介绍加减电子法、带张力环稠合法、键长缩短法和金属螫合法四种可使不平面之环辛四烯成为平面方法。然而,随有机合成方法之不断进展,在将来可能出现更多改变环辛四烯不平面结构的方法。我们在此文章提出化合物98即为一个可使环辛四烯成为平面的例子。98之合成将成为有机合成化学家的一个新的挑战。     

Molecular Forcefield Methods for Describing Energetic Molecular Crystals: A Review

Energetic molecular crystals are widely applied for military and civilian purposes, and molecular forcefields (FF) are indispensable for treating the microscopic issues therein. This article reviews the three types of molecular FFs that are applied widely for describing energetic crystals—classic FFs, consistent FFs, and reactive FFs (ReaxFF). The basic principle of each type of FF is briefed and compared, with the application introduced, predicting polymorph, morphology, thermodynamics, vibration spectra, thermal property, mechanics, and reactivity. Finally, the advantages and disadvantages of these FFs are summarized, and some directions of future development are suggested.     

A Symmetry adapted tessellation of the GEPOL surface: applications to molecular properties in solution

A procedure to partition the GEPOL molecular surface into tesserae that respects the molecular symmetry constraints is presented. Using this method it is possible to build a solvent reaction field for the Polarizable Continuum Model with the same symmetry of the nuclear potential. Several applications are reported and discussed to evaluate the performance of this new procedure. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1262–1272, 2001     

轮烷研究－从超分子组装到分子器件

轮烷是一类由两端带有大的基团的线性分子和有机环化合物组成的互相锁连的分子化合物。主要综述了近年来这类超分子化合物的合成方法进展、在合成中的应用及其作为分子器件方面的研究进展。     

Influence of Intermolecular Vibrations on the Electronic Coupling in Organic Semiconductors: The Case of Anthracene and Perfluoropentacene

We have performed classical molecular dynamics simulations and quantum‐chemical calculations on molecular crystals of anthracene and perfluoropentacene. Our goal is to characterize the amplitudes of the room‐temperature molecular displacements and the corresponding thermal fluctuations in electronic transfer integrals, which constitute a key parameter for charge transport in organic semiconductors. Our calculations show that the thermal fluctuations lead to Gaussian‐like distributions of the transfer integrals centered around the values obtained for the equilibrium crystal geometry. The calculated distributions have been plugged into Monte‐Carlo simulations of hopping transport, which show that lattice vibrations impact charge transport properties to various degrees depending on the actual crystal structure.     

Molecular weight distributions of linear polymers: Detailed analysis from GPC data

The GPC method is used widely to measure molecular weights of linear polymers. High-quality GPC data contains detailed information on many aspects of the polymer's molecular weight distribution (MWD). This information can be extracted from the data using computer analysis. Equations have been derived for the two simplest MWD functions in the GPC coordinates: the Flory function (one growing polymer chain produces one polymer molecule), and for the case when two polymer radicals combine into one polymer molecule. The equations were used to analyze MWD of two classes of polymers. The first class includes polymers with narrow MWD: polyethylene, ethylene-propylene and ethylene-hexene copolymers, syndiotactic polystyrene, and radical polystyrene. The second class includes polymers with broad MWD: ethylene copolymers and polypropylene produced with heterogeneous, Ti-based catalysts. The examples demonstrate that the resolution of complex GPC curves into their constitutents serve as an important source of information about kinetics of polymerization reactions. © 1995 John Wiley & Sons, Inc.     

Moving targets: recognition of alkyl groups

Alkyl chains can adopt seemingly unusual conformations, such as helices, when bound to natural and synthetic hydrophobic receptors. This plasticity allows the alkanes to assume shapes that are congruent to the receptor's space and fill that space properly. We describe here the use of cavitands and capsules as tools that expose the forces involved in the molecular recognition of hydrocarbons. Studies using NMR spectroscopy reveal how attractive interactions and solvophobic forces are maximized in solution through unprecedented contortions of alkanes and hint at a new generation of nanoscale mechanical devices.     

Morphological similarity: A 3D molecular similarity method correlated with protein-ligand recognition

Recognition of small molecules by proteins depends on three-dimensional molecular surface complementarity. However, the dominant techniques for analyzing the similarity of small molecules are based on two-dimensional chemical structure, with such techniques often outperforming three-dimensional techniques in side-by-side comparisons of correlation to biological activity. This paper introduces a new molecular similarity method, termed morphological similarity (MS), that addresses the apparent paradox. Two sets of molecule pairs are identified from a set of ligands whose protein-bound states are known crystallographically. Pairs that bind the same protein sites form the first set, and pairs that bind different sites form the second. MS is shown to separate the two sets significantly better than a benchmark 2D similarity technique. Further, MS agrees with crystallographic observation of bound ligand states, independent of information about bound states. MS is efficient to compute and can be practically applied to large libraries of compounds.     

X-ray Structures of Three Penem Antibiotics: Molecular Mechanical and Dynamic Aspects

The structures of three -lactam penem antibiotics—i.e. the sodium[5R-[5,6(R*)]]-6-(1-hydroxyethyl)-7-oxo-3-[[(1-pyrrolidinylthioxomethyl)thio]methyl]-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (compound 1), the [5R-[3(S*),5,6(R*)]]-3-[[2-(aminocarbonyl)-1-pyrrolidinyl] methyl]-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (compound 2), and the [5R-[5,6(R*)]]-3-[[(2-amino-2-oxoethyl) methylamino]methyl]-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (compound 3)—have been determined by X-ray analyses. In the crystal lattice two conformational isomers of 1 are present, which differ from each other in the spatial arrangement of the dithiocarbamate chain. Compounds 2 and 3 are in zwitterionic form, being the hydrogen of the carboxylic acid moved to the amino nitrogen of the chain at C2. This hydrogen atom, in both molecules, forms intramolecular hydrogen bonds with an oxygen atom of the carboxylate moiety and with the oxygen atom of the amido group of the side chain. The 3D structures of 1, 2, and 3 have been compared with those of previously reported -lactam penem antibiotics. Particularly, the Woodward parameter and the Cohen distance, which are considered important in determining the antibiotic activity, have been discussed. Least-squares minimizations (RMS) of the distances between nuclei of selected pairs of atoms defining the pharmacological pattern have been performed, comparing five common antibiotics (imipenem, ritipenem, cephaloridine, amoxycillin, and benzylpenicillin) with our compounds. Finally, molecular dynamics calculations have been carried out on the three penem antibiotics at different temperatures. The conformational behavior of the hydroxyethyl chain, the carboxylate group, and the chain at C2 is discussed by considering the variation of some selected dihedral angles.     

EUDOC: a computer program for identification of drug interaction sites in macromolecules and drug leads from chemical databases

The completion of the Human Genome Project, the growing effort on proteomics, and the Structural Genomics Initiative have recently intensified the attention being paid to reliable computer docking programs able to identify molecules that can affect the function of a macromolecule through molecular complexation. We report herein an automated computer docking program, EUDOC, for prediction of ligand-receptor complexes from 3D receptor structures, including metalloproteins, and for identification of a subset enriched in drug leads from chemical databases. This program was evaluated from the standpoints of force field and sampling issues using 154 experimentally determined ligand-receptor complexes and four "real-life" applications of the EUDOC program. The results provide evidence for the reliability and accuracy of the EUDOC program. In addition, key principles underlying molecular recognition, and the effects of structural water molecules in the active site and different atomic charge models on docking results are discussed. Copyright 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1750-1771, 2001     

Polyatomic molecular liquids under extreme compression: facts,models, and a few predictions

Early work by Siringo, Pucci and March (Phys. Rev. B, 37, 2491 (1988)) studied solid I₂ under high pressure at T = 0. Their conclusion was that insulating crystalline I₂ at low pressures eventually transformed into a molecular metal. This has subsequently been confirmed experimentally. Later studies by Weir et al. (Phys. Rev. Lett., 76, 1860 (1996)) on solid H₂ under pressure point in the same direction, though in the solid phase the metallic state has still not been achieved at low temperatures. However, in the liquid phase, an insulating metallic transition has been proposed, as in solid iodine, again on the basis of experimental high-pressure studies. Here, attention is shifted to some polyatomic molecules, such as the 10-electron series H₂O, NH₃ and CH₄. Particular attention is focused on the measured Hugoniots of the polyatomic molecular liquids.     

Scorpiands: Quinquedentate Ligands that Couple the Rigidity of Cyclam and the Flexibility of a Coordinating Side Chain

This review tells the story of scorpiands, polyamine ligands which, when specifically stimulated, act as scorpions, and of their metal complexes, scorpiates. Scorpiands consist of a tetramine macrocycle (typically cyclam) capable of firmly including a transition metal and of a side chain ending with a nitrogen containing coordinating group: under unperturbed conditions the coordinating group is bound to the metal (ON), but on addition of acid the nitrogen is protonated and comes off the metal (OFF). Alternating acid/base addition makes the side chain move imitating the tail of a scorpion that bites a prey firmly immobilized by the claws. Occurrence of the ON-OFF motion is monitored by the colour change of the scorpiate complexes associated to the change of coordination or by fluorescence quenching/restoring when a light-emitting substituent is linked to the side arm. Scorpiate complexes can be considered optical molecular switches and, from a different standpoint, molecular machines able to convert chemical energy into mechanical work.     

Effect of homopolymer matrix on diblock copolymer grafted nanoparticle conformation and potential of mean force: A molecular simulation study

We study the effect of homopolymer A or B matrix on the conformations and effective interactions of AB diblock copolymer grafted particles using coarse‐grained molecular dynamics simulations. In an A homopolymer matrix we observe patchy conformations within the AB diblock copolymer grafted layer, where the number of B patches is controlled by the A‐A attractive interaction strength. In a B homopolymer matrix the grafted particle takes on a core‐corona conformation, where the inner A block aggregates near the particle surface and the outer B block forms a corona that interacts with the B matrix. The potential of mean force (PMF) between two particles in an A homopolymer matrix has a long‐ranged attractive well with a minima at intermediate distances corresponding to the location of the outer B block patches. The PMF between two particles in a B homopolymer matrix has an attractive well at short interparticle distances corresponding to the size of the inner A block. We isolate the contribution of the homopolymer matrix on the PMF between the two diblock copolymer grafted particles, by deducting the PMF in the absence of a matrix, assuming the contributions of the grafted particle and matrix to the PMF to be additive. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 76–88     

Structural and Dynamic Basis of Human Cytochrome P450 7B1: A Survey of Substrate Selectivity and Major Active Site Access Channels

Cytochrome P450 (CYP) 7B1 is a steroid cytochrome P450 7α‐hydroxylase that has been linked directly with bile salt synthesis and hereditary spastic paraplegia type 5 (SPG5). The enzyme provides the primary metabolic route for neurosteroids dehydroepiandrosterone (DHEA), cholesterol derivatives 25‐hydroxycholesterol (25‐HOChol), and other steroids such as 5α‐androstane‐3β,17β‐diol (anediol), and 5α‐androstene‐3β,17β‐diol (enediol). A series of investigations including homology modeling, molecular dynamics (MD), and automatic docking, combined with the results of previous experimental site‐directed mutagenesis studies and access channels analysis, have identified the structural features relevant to the substrate selectivity of CYP7B1. The results clearly identify the dominant access channels and critical residues responsible for ligand binding. Both binding free energy analysis and total interaction energy analysis are consistent with the experimental conclusion that 25‐HOChol is the best substrate. According to 20 ns MD simulations, the Phe cluster residues that lie above the active site, particularly Phe489, are proposed to merge the active site with the adjacent channel to the surface and accommodate substrate binding in a reasonable orientation. The investigation of CYP7B1–substrate binding modes provides detailed insights into the poorly understood structural features of human CYP7B1 at the atomic level, and will be valuable information for drug development and protein engineering.