Conformational Polymorphism in G-tetraplex Structures: Strand Reversal by Base Flipover or Sugar Flipover

Guanine rich sequences adopt a variety of four stranded structures, which differ in strand orientation and conformation about the glycosidic bond even though they are all stabilised by Hoogsteen hydrogen bonded guanine tetrads. Detailed model building and molecular mechanics calculations have been carried out to investigate various possible conformations of guanines along a strand and different possible orientations of guanine strands in a G-tetraplex structure. It is found that for an oligo G stretch per se, a parallel four stranded structure with all guanines in anti conformation is favoured over other possible tetraplex structures. Hence an alternating syn-anti arrangement of guanines along a strand is likely to occur only in folded back tetraplex structures with antiparallel G strands. Our study provides a theoretical rationale for the observed alternation of glycosidic conformation and the inverted stacking arrangement arising from base flipover, in antiparallel G-tetraplex structures and also highlights the various structural features arising due to different types of strand orientations. The molecular mechanics calculations help in elucidating the various interactions which stabilize different G-tetraplex structures and indicate that screening of phosphate charge by counterions could have a dramatic effect on groove width in these four stranded structures.

Conformational polymorphism in G-tetraplex structures: strand reversal by base flipover or sugar flipover

Guanlne rich sequences adopt a variety of four stranded structures, which differ in strand orientation and conformation about the glycosldic bond even though they are all stabilised by Hoogsteen hydrogen bonded guanlne tetrads. Detailed model building and molecular mechanics calculations have been carried out to investigate various possible conformations of guanlnes along a strand and different possible orientations of guanlne strands In a G-tetraplex structure. It is found that for an ollgo G stretch per se, a parallel four stranded structure with all guanines In anti conformation is favoured over other possible tetraplex structures. Hence an alternating syn-anti arrangement of guanlnes along a strand is likely to occur only in folded back tetraplex structures with antiparallel G strands. Our study provides a theoretical rationale for the observed alternation of glycosldic conformation and the inverted stacking arrangement arising from base filpover, In antlparallel G-tetraplex structures and also highlights the various structural features arising due to different types of strand orientations. The molecular mechanics calculations help in elucidating the various interactions which stabilize different G-tetraplex structures and indicate that screening of phosphate charge by counterions could have a dramatic effect on groove width in these four stranded structures.

Diastereospecific Coupling of Imines by Low-Valent Titanium: An Experimental and Computational Study

The reaction of phenylsilane (PhSiH3) and titanium(IV) isopropoxide Ti(OiPr)(4)] generates low-valent titanium alkoxides that reduce and reductively couple imines. The C-C coupling reaction is diastereospecific, with exclusive formation of the (+/-)-isomer. The yield is dependent on the concentration of titanium(IV) isopropoxide used. Using imines with varying electronic demand revealed that the coupling is most efficient for unsubstituted imines. The involvement of a trimeric titanium biradical species is invoked to explain the observed concentration dependence and diastereospecificity in the reaction. Multilayer ONIOM (''our own n-layered integrated molecular orbital and molecular mechanics'') calculations were carried out on the plausible intermediates involved by using the Guassian 09 suite of programs. Formation of the trimeric biradical species leading to the formation of the (+/-)-isomer is more favored than formation of the trimeric biradical species, which leads to the meso-isomer. Similar calculations with dimeric intermediates do not predict the (+/-)-selectivity. Mass spectral analysis of the reaction mixture indicates the presence of a trimeric titanium alkoxide species.

Analysis of geometric and strain effects in homo-Diels-Alder reactions

Molecular mechanics calculations have been carried out to quantify the key geometric and strain effects which are likely to control the homo-Diels-Alder reactivity of 1,4-dienes. The criteria considered include C1..C5 and C2..C4 distances in the diene, twist angle of the two pi units, and the magnitude of strain increase as a result of cycloaddition. By first considering these factors in a number of non-conjugated dienes with known reactivity, the ranges of values within which the reaction is favoured are proposed. Calculations are also reported on several substrates which have not been investigated so far. Promising systems for experimental study are suggested which, in addition to being intrinsically interesting, would place the present proposals on a firm basis.

Docking and free energy simulations to predict conformational domains involved in hCG-LH receptor interactions using recombinant antibodies

Single chain fragment variables (ScFvs) have been extensively employed in studying the protein-protein interactions. ScFvs derived from phage display libraries have an additional advantage of being generated against a native antigen, circumventing loss of information on conformational epitopes. In the present study, an attempt has been made to elucidate human chorionic gonadotropin (hCG)-luteinizing hormone (LH) receptor interactions by using a neutral and two inhibitory ScFvs against hCG. The objective was to dock a computationally derived model of these ScFvs onto the crystal structure of hCG and understand the differential roles of the mapped epitopes in hCG-LH receptor interactions. An anti-hCG ScFv, whose epitope was mapped previously using biochemical tools, served as the positive control for assessing the quality of docking analysis. To evaluate the role of specific side chains at the hCG-ScFv interface, binding free energy as well as residue interaction energies of complexes in solution were calculated using molecular mechanics Poisson-Boltzmann/surface area method after performing the molecular dynamic simulations on the selected hCG-ScFv models and validated using biochemical and SPR analysis. The robustness of these calculations was demonstrated by comparing the theoretically determined binding energies with the experimentally obtained kinetic parameters for hCG-ScFv complexes. Superimposition of hCG-ScFv model onto a model of hCG complexed with the 51-266 residues of LH receptor revealed importance of the residues previously thought to be unimportant for hormone binding and response. This analysis provides an alternate tool for understanding the structure-function analysis of ligand-receptor interactions. Proteins 2011;79:3108-3122. (C) 2011 Wiley-Liss, Inc.

Self-Assembly of Metallamacrocycles Using a Dinuclear Organometallic Acceptor: Synthesis, Characterization, and Sensing Study

A dinuclear organometallic acceptor 4,4'-bis[trans-Pt(PEt(3))(2)(O(3)SCF(3))(ethynyl)]biphenyl (1) containing Pt-ethynyl functionality is synthesized. Multinuclear NMR ((1)H, (31)P, and (13)C), infrared (IR), and electrospray ionization mass spectrometry (ESI-MS) including single-crystal X-ray diffraction analysis established the formation of 1. Equimolar treatment of acceptor 1 separately with three different ``clip'' type ditopic donors (L(a)-L(c)) yielded [2 + 2] self-assembled three metallamacrocycles 2a-2c, respectively. These macrocycles were characterized by various spectroscopic techniques, and their sizes/shapes were obtained through geometry optimization using molecular mechanics universal force field (MMUFF) simulations. Attachment of unsaturated ethynyl functionality to biphenyl building unit helped to make the macrocycles (2a-2c) pi-electron rich and thereby fluorescent in nature. Furthermore, 2c in solution has been examined to be suitable for sensing electron-deficient nitroaromatic like picric acid, which is often considered as a secondary chemical explosive. The fluorescence study of 2c showed a marked quenching of initial emission intensity upon titrating with picric acid (PA), and it exhibited the largest fluorescence quenching response with high selectivity among various other electron deficient aromatic compounds tested.

Pt-6(II) nanoscopic cages with an organometallic backbone as sensors for picric acid

An organometallic building block 1,3,5-tris(4-trans-Pt(PEt3)(2)I(ethynyl)phenyl)benzene (1) incorporating Pt-ethynyl functionality has been synthesized and characterized. 2 + 3] self-assembly of its nitrate analogue 1,3,5-tris(4-trans-Pt(PEt3)(2)(ONO2)(ethynyl)phenyl)benzene (2) with ``clip'' type bidentate donors (L-1-L-3) separately afforded three trigonal prismatic architectures (3a-3c), respectively. All these prisms were characterized and their shapes/sizes are predicted through geometry optimization employing molecular mechanics universal force field (MMUFF) simulation. The extended p-conjugation including the presence of Pt-ethynyl functionality makes them electron rich as well as luminescent in nature. Macrocycles 3b and 3c exhibit fluorescence quenching in solution upon addition of picric acid PA], which is a common constituent of many explosives. Interestingly, the non-responsive nature of fluorescent intensity towards other electron-deficient nitro-aromatic explosives (NAEs) makes them promising selective sensors for PA with a detection limit predicted to be ppb level. Furthermore, solid-state quenching of fluorescent intensity of the thin film of 3b upon exposure to saturated vapor of picric acid has drawn special attention for infield applications.

VIBRATIONAL CHARACTERISTICS OF ZIGZAG, ARMCHAIR AND CHIRAL CANTILEVER SINGLE-WALLED CARBON NANOTUBES

Finite element analysis has been performed to study vibrational characteristics of cantilever single walled carbon nanotubes. Finite element models are generated by specifying the C-C bond rigidities, which are estimated by equating energies from molecular mechanics and continuum mechanics. Bending, torsion, and axial modes are identified based on effective mass for armchair, zigzag and chiral cantilever single walled carbon nanotubes, whose Young's modulus is evaluated from the bending frequency. Empirical relations are provided for frequencies of bending, torsion, and axial modes.

A novel method for studying the buckling of nanotubes considering geometrical imperfections

Buckling of nanotubes has been studied using many methods such as molecular dynamics (MD), molecular mechanics, and continuum-based shell theories. In MD, motion of the individual atoms is tracked under applied temperature and pressure, ensuring a reliable estimate of the material response. The response thus simulated varies for individual nanotubes and is only as accurate as the force field used to model the atomic interactions. On the other hand, there exists a rich literature on the understanding of continuum mechanics-based shell theories. Based on the observations on the behavior of nanotubes, there have been a number of shell theory-based approaches to study the buckling of nanotubes. Although some of these methods yield a reasonable estimate of the buckling stress, investigation and comparison of buckled mode shapes obtained from continuum analysis and MD are sparse. Previous studies show that the direct application of shell theories to study nanotube buckling often leads to erroneous results. The present study reveals that a major source of this error can be attributed to the departure of the shape of the nanotube from a perfect cylindrical shell. Analogous to the shell buckling in the macro-scale, in this work, the nanotube is modeled as a thin-shell with initial imperfection. Then, a nonlinear buckling analysis is carried out using the Riks method. It is observed that this proposed approach yields significantly improved estimate of the buckling stress and mode shapes. It is also shown that the present method can account for the variation of buckling stress as a function of the temperature considered. Hence, this can prove to be a robust method for a continuum analysis of nanosystems taking in the effect of variation of temperature as well.

Electronically nonadiabatic decomposition mechanisms of clusters of zinc and dimethylnitramine

Electronically nonadiabatic decomposition mechanisms of dimethylnitramine (DMNA) in presence of zinc metal clusters are explored. Complete active space self-consistent field (CASSCF) calculation is employed for DMNA-Zn and ONIOM (Our own N-layered integrated molecular orbital and molecular mechanics) methodology is coupled with CASSCF methodology for DMNA-Zn-10 cluster. Present computational results show that DMNA-Zn clusters undergo electronically nonadiabatic reactions, rendering nitro-nitrite isomerization followed by NO elimination. The overall reactions are also found to be highly exothermic in nature. This is the first report on electronically nonadiabatic decomposition pathways of DMNA-Zn-n neutral clusters. (C) 2014 Elsevier B.V. All rights reserved.

Template-free coordination-driven self-assembly of discrete hexanuclear prismatic cages employing half-sandwich octahedral Ru-2(II) acceptors and triimidazole donors

Coordination-driven self-assembly of dinuclear half-sandwich p-cymene ruthenium(II) complexes Ru-2(mu-eta(4)-C2O4)(CH3OH)(2)(eta(6)-p-cymene)(2)](O3SCF3)(2) (1a) and Ru-2(mu-eta(4)-C6H2O4)(CH3OH)(2)(eta(6)-p-cymene)(2)](O3SCF3)(2) (1b) separately with imidazole-based tritopic donors (L-1-L-2) in methanol yielded a series of hexanuclear 3+2] trigonal prismatic cages (2-5), respectively L-1 = 1,3,5-tris(imidazole-1-yl) benzene; L-2 = 4,4',4 `'-tris(imidazole-1-yl) triphenylamine]. All the self-assembled cages 2-5 were characterized by various spectroscopic techniques (multinuclear NMR, Infra-red and ESI-MS) and their sizes, shapes were obtained through geometry optimization using molecular mechanics universal force field (MMUFF) computation. Despite the possibility due to the free rotation of donor sites of imidazole ligands, of two different atropoisomeric prismatic cages (C-3h or C-s) and polymeric product, the self-selection of single (C(3)h) conformational isomeric cages as the only product is a noteworthy observation. (C) 2015 Elsevier B.V. All rights reserved.

Coarse-Grained Molecular Dynamics Simulation of the Aggregation Properties of Multiheaded Cationic Surfactants in Water

The aggregation property of multiheaded surfactants has been investigated by constant pressure molecular dynamics (MD) simulation in aqueous medium. The model multiheaded surfactants contain more than one headgroup (x = 2, 3, and 4) for a single tail group. This increases the hydrophilic charge progressively over the hydrophobic tail which has dramatic consequences in the aggregation behavior. In particular, we have looked at the change in the aggregation property such as critical micellar concentration (cmc), aggregation number, and size of the micelles for the multiheaded surfactants in water. We find with increasing number of headgroups of the Multiheaded surfactants that the cmc values increase and the aggregation numbers as well as the size of the micelles decrease. These trends are in agreement with the experimental findings as reported earlier with x = 1, 2, and 3. We also predict the aggregation properties of multiheaded surfactant With four headgroups (x = 4) for which no experimental studies exist yet.

An Insight to the Dynamics of Conserved Water Molecular Triad in IMPDH II (Human): Recognition of Cofactor and Substrate to Catalytic Arg 322

Inosine 5' monophosphate dehydrogenase (IMPDH II) is a key enzyme involved in the de novo biosynthesis pathway of purine nucleotides and is also considered to be an excellent target for cancer inhibitor design. The conserve R 322 residue (in human) is thought to play some role in the recognition of inhibitor and cofactor through the catalytic D 364 and N 303. The 15 ns simulation and the water dynamics of the three different PDB structures (1B3O, 1NF7, and 1NFB) of human IMPDH by CHARMM force field have clearly indicated the involvement of three conserved water molecules (W-L, W-M, and W-C) in the recognition of catalytic residues (R 322, D 364, and N 303) to inhibitor and cofactor. Both the guanidine nitrogen atoms (NH1 and NH 2) of the R 322 have anchored the di- and mono-nucleotide (cofactor and inhibitor) binding domains via the conserved W-C and W-L water molecules. Another conserved water molecule W-M seems to bridge the two domains including the R 322 and also the W-C and W-L through seven centers H-bonding coordination. The conserved water molecular triad (W-C - W-M - W-L) in the protein complex may thought to play some important role in the recognition of inhibitor and cofactor to the protein through R 322 residue.

Two-Phase Thermodynamic Model for Efficient and Accurate Absolute Entropy of Water from Molecular Dynamics Simulations

Presented here is the two-phase thermodynamic (2PT) model for the calculation of energy and entropy of molecular fluids from the trajectory of molecular dynamics (MD) simulations. In this method, the density of state (DoS) functions (including the normal modes of translation, rotation, and intramolecular vibration motions) are determined from the Fourier transform of the corresponding velocity autocorrelation functions. A fluidicity parameter (f), extracted from the thermodynamic state of the system derived from the same MD, is used to partition the translation and rotation modes into a diffusive, gas-like component (with 3Nf degrees of freedom) and a nondiffusive, solid-like component. The thermodynamic properties, including the absolute value of entropy, are then obtained by applying quantum statistics to the solid component and applying hard sphere/rigid rotor thermodynamics to the gas component. The 2PT method produces exact thermodynamic properties of the system in two limiting states: the nondiffusive solid state (where the fluidicity is zero) and the ideal gas state (where the fluidicity becomes unity). We examine the 2PT entropy for various water models (F3C, SPC, SPC/E, TIP3P, and TIP4P-Ew) at ambient conditions and find good agreement with literature results obtained based on other simulation techniques. We also validate the entropy of water in the liquid and vapor phases along the vapor-liquid equilibrium curve from the triple point to the critical point. We show that this method produces converged liquid phase entropy in tens of picoseconds, making it an efficient means for extracting thermodynamic properties from MD simulations.

Ab initio molecular orbital calculations on ion-molecule and ion pair-molecule complexes of the water-lithium cyanide system

Ab initio molecular orbital (MO) calculations with the 3-21G and 6-31G basis sets were performed on a series of ion-molecule and ion pair-molecule complexes for the H2O + LiCN system. Stabilisation energies (with counter-poise corrections), geometrical parameters, internal force constants and harmonic vibrational frequencies were evaluated for 16 structures of interest. Although the interaction energies are smaller, the geometries and relative stabilities of the monohydrated contact ion pair are reminiscent of those computed for the complexes of the individual ions. Thus, interaction of the oxygen lone pair with lithium leads to a highly stabilised C2v structure, while the coordination of water to the cyanide ion involves a slightly non-linear hydrogen bond. Symmetrical bifurcated structures are computed to be saddle points on the potential energy surface, and to have an imaginary frequency for the rocking mode of the water molecule. On optimisation the geometries of the solvent shared ion pair structures (e.g. Li+cdots, three dots, centered OH2cdots, three dots, centered CN−) revealed a proton transfer from the water molecule leading to hydrogen bonded forms such as Li-O-Hcdots, three dots, centered HCN. The variation in the force constants and harmonic frequencies in the various structures considered are discussed in terms of ion-molecular and ion pair-molecule interactions.