Effect Of Conformational Changes Research Articles

ChemInform Abstract: Conformational and Substituent Effects on Spin Distributions in Porphyrin Cation Radicals

Optical, redox, EPR, and ENDOR results are presented for zinc meso-tetraphenyltetrabenzoporphyrin (ZnTPTBP). The molecule is a hybrid of the common synthetic porphyrins zinc tetraphenylporphyrin (ZnTPPP) and zinc tetrabenzoporphyrin (ZnTBP). The consequences of the additional peripheral substituents in the hybrid are evident in a previously obtained x-ray structure of ZnTPTBP that shows the macrocycle to be severely puckered to minimize steric interactions between the substituents. The cumulative effects of conformational changes and substituent addition are reflected in the red-shifted optical spectrum and ease of oxidation of the neutral compound, and in a shift of unpaired spin density from a{sub 1u} (ZnTBP) to a{sub 2u} (ZnTPP) character in the radical. Significant spin density is found to delocalize onto the phenyl substituents of ZnTPTBP{sup {sm bullet}+} and illustrates the shortening of the effective distance between donor and acceptor that may occur in biomimetic complexes used to investigate the distance and energy dependence of electron transfer.

Simulating Efflux Pumps: The Extrusion Mechanism of Substrates

Bacteria use multidrug efflux pumps to extrude toxic substrates through their cell membranes. The RND transporters of the AcrAB-TolC (E.Coli) and MexAB-OprM (P.Aeruginosa) systems are able to export structurally and chemically different substrates, being responsible of multidrug resistance. While the energy conversion takes place in the transmembrane domain of AcrB and MexB, the energy is transducted towards the periplasmic part and used there to initiate what is believed to be a three-cyclic peristaltic pumping. Using different computational methods like adaptive bias force (ABF) and targeted molecular dynamics (TMD), we have investigated the mechanism of substrate uptake and pumping. With ABF we have studied the passage of antibiotics from the periplasm and protein-lipid interface into the inner pore of the pump, while TMD has been used to assess the effect of conformational changes on the extrusion of drugs (located into one of the proposed binding pockets). Finally, analysis of water distribution in the transmembrane region represents an important step to identify features of the energy transduction process. Comparison between the active pumps AcrB and MexB (which show different resistance patterns despite their homology) provide insights into the microscopic details of their functioning.View Large Image | View Hi-Res Image | Download PowerPoint Slide

Differential electronic states observed during A–B DNA duplex conformational transitions

The conformational transitions and the sensitivity of the DNA structure to the surrounding environment are very relevant to its chemical and biological function and potential applications in nano-technology. Different conformations of DNA, even with the same sequence, exhibit different electronic structures, resulting in different conduction properties. We present theoretical work on the dynamical features of electronic states in the A- to B-type transition of a model DNA duplex of d(CGCGCGCGCG)2 (10 base-pairs, 628 atoms) as the molecule undergoes conformational changes and thermal fluctuations at room temperature. We couple state-of-the art empirical force field molecular dynamics (MD) simulations with an ab initio electronic structure method based on a density-functional theory, called FIREBALL. For the A–B transition, we calculated the effects of conformational changes on the electronic structure for each snapshot obtained from nanosecond MD simulations.

Pin1 as an anticancer drug target

Pin1 specifically catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro bonds and plays an important role in many cellular events through the effects of conformational change on the function of its biological substrates, including cell division cycle 25 C (Cdc25C), c-Jun and p53. Pin1 is overexpressed in many human cancer tissues, including breast, prostate and lung cancer. Its expression correlates with cyclin D1 levels, which contribute to cell transformation. Overexpression of Pin1 promotes tumor growth, while inhibition of Pin1 causes tumor cell apoptosis. Pin1 plays an important role in oncogenesis and therefore may serve as an effective anticancer target. Many inhibitors of Pin1 have been discovered, including several classes of designed inhibitors (alkene isosteres, reduced amides, indanyl ketones) and natural products (juglone, pepticinnamin E analogues, PiB and its derivatives obtained from a library screen). Pin1 inhibitors could be used as a novel type of anticancer drug by blocking cell cycle progression. Therefore, Pin1 represents a new diagnostic and therapeutic anticancer drug target.

Evidence for Dual Pathway in Through‐Space Singlet Energy Transfers in Flexible Cofacial Bisporphyrin Dyads

Flexible "pacman" scaffolds built upon a calix[4]arene platform bearing a [18]crown-6 ether and either two OH functions or two OPr groups at the lower rim have been used to generate donor-acceptor (D-A) dyads incorporating a zinc-porphyrin donor and a free-base porphyrin acceptor. Through-space singlet energy transfer (SET) in the D-A dyads was studied by time-resolved fluorescence spectroscopy. Although the effects of conformational changes are well documented when the chromophores switch from a non-cofacial to a cofacial arrangement, little is known about flexible pacman scaffolds in which the changes are limited to the distance between the chromophores. The known SET rates for reported, geometrically well-defined, rigid pacman D-A dyads were used as calibration to estimate the D-A distances in the flexible pacman dyads. Due to the flexibility of the calix[4]arene spacer, the D-A dyads adopt a "closed" or "open" geometry that is tuned by intramolecular hydrogen bonds (O--H...[18]crown-6 ether) and by solvent interactions. Changes in the SET rates between the open and closed geometries were surprisingly less dramatic than expected, and are explained by a dual SET pathway that is specific to the calix[4]arene platform. Time-resolved fluorescence studies support the hypothesis that, for the "open" conformer, the preferred through space SET pathway (i.e., at the shortest distance) is located within the calix[4]arene cavity through the cofacial phenyl groups. For the "closed" conformer, the preferred through space SET route is located between the zinc and free-base porphyrins.

Superoxide Radical Anion Adduct of 5,5-Dimethyl-1-pyrroline N-Oxide. 4. Conformational Effects on the EPR Hyperfine Splitting Constants

Spin trapping has been commonly employed in the detection of superoxide radical anion in chemical and biological systems; hence, accurate interpretation of the hyperfine splitting constants (hfsc's) arising from the O(2)(*-) adducts (also referred to as hydroperoxyl (HO(2)(*)) radical adducts) of various nitrones is important. In this work, the nature of the relevant hfsc's was investigated by examining the effect of conformational changes in the hydroperoxyl moiety of the O(2)(*-) adducts of 5,5-dimethyl-1-pyrroline N-oxide (DMPO), 5-ethoxycarbonyl-5-methyl-1-pyrroline N-oxide (EMPO), 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO), 5-carbamoyl-5-methyl-1-pyrroline N-oxide (AMPO), and 7-oxa-1-azaspiro[4.4]non-1-en-6-one N-oxide, (CPCOMPO) on the magnitude of a(N), a(beta-H), and a(gamma-H). Conformational change around the substituents and their effect on the hfsc's were also explored. Results indicate that a(beta-H) is most sensitive to conformational changes of the hydroperoxyl and substituent groups relative to hfsc's of other nuclei. The orbital overlap between the C-H sigma-orbital and the SOMO of the nitroxyl nitrogen plays a crucial factor in determining the magnitude of the a(beta-H). The hfsc values for the O(2)(*-) adducts were predicted with high accuracy by using a low-cost computational method at the PCM(water)/BHandHLYP/EPR-III//B3LYP/6-31G* level of theory without taking into account the explicit water interaction.

Structural effects on the conformational transition of transferrin induced by binding of flavonoids with different numbers and positions of hydroxyl groups

The effects of conformational changes to transferrin induced by the binding of flavonoids with different numbers and positions of hydroxyl groups were explored using spectroscopic and molecular modeling methods. The flavonoid hydroxyl group is not necessary for conformation changes of transferrin. However, the binding ability was found to increase with increasing numbers of hydroxyl groups and further conformational changes were observed. By molecular modeling calculations, intermolecular energy including van der Waals and electrostatic interactions, together with hydrogen bonding are found to have important roles in binding of flavonoids to transferrin. Additionally, the positions of the hydroxyl groups also affect the binding ability because they can alter the relative acidity of the hydroxyl groups, thereby changing the hydrogen bonding ability. Our results have indicated a mechanism for the interactions between flavonoids and transferrin, and provide information for possible flavonoid modification and design of methods to deliver drug molecules via transferrin to target tissues and cells effectively.

Backbone Motions of Free and Pheromone-Bound Major Urinary Protein I Studied by Molecular Dynamics Simulation

Molecular motions of free and pheromone-bound mouse major urinary protein I, previously investigated by NMR relaxation, were simulated in 30 ns molecular dynamics (MD) runs. The backbone flexibility was described in terms of order parameters and correlation times, commonly used in the NMR relaxation analysis. Special attention was paid to the effect of conformational changes on the nanosecond time scale. Time-dependent order parameters were determined in order to separate motions occurring on different time scales. As an alternative approach, slow conformational changes were identified from the backbone torsion angle variances, and "conformationally filtered" order parameters were calculated for well-defined conformation states. A comparison of the data obtained for the free and pheromone-bound protein showed that some residues are more rigid in the bound form, but a larger portion of the protein becomes more flexible upon the pheromone binding. This finding is in general agreement with the NMR results. The higher flexibility observed on the fast (fs-ps) time scale was typically observed for the residues exhibiting higher conformational freedom on the ns time scale. An inspection of the hydrogen bond network provided a structural explanation for the flexibility differences between the free and pheromone-bound proteins in the simulations.

Effect of conformational changes and differences of proteins on frictional properties of poly(vinyl alcohol) hydrogel

In this study, albumin or γ-globulin, both of which are included in natural synovial fluid, was used as an additive into lubricants to investigate the ability to reduce the friction for poly(vinyl alcohol) hydrogel in mixed lubrication. It was found from a measurement in circular dichroism that albumin contains a large amount of α-helix structure and γ-globulin contains a large amount of β-sheet structure. The lubricant containing only albumin showed low friction compared to the lubricant containing only γ-globulin. The effect of protein boundary film was clarified by changing lubricant. Albumin kept the friction low after changing from γ-globulin used at initial rubbing, but γ-globulin increased the friction after changing from albumin at initial rubbing. From a sliding distance of 600 m, albumin showed lower friction but γ-globulin showed higher friction. Therefore, in the case of friction decreasing, γ-globulin forms a tight adsorbed layer and subsequently albumin forms a layer with low shearing strength. Hence, it is important to apply the adsorption layer of γ-globulin at the bottom and make a layered structure composed of albumin and γ-globulin to reduce both friction and wear.

The effects of backbone conformation on hydration and proton transfer in the ‘short-side-chain’ perfluorosulfonic acid membrane

Presented here is a first principles based molecular modeling investigation of the effects of conformational changes in the backbone on hydration and proton transfer in the short-side-chain perfluorosulfonic acid fuel cell membrane under minimal hydration conditions. Extensive searches for minimum energy structures (at the B3LYP/6-311G ⁎⁎ level) of the two pendant side chain polymeric fragment: CF 3CF(–O(CF 2) 2SO 3H)–(CF 2) 7–CF(–O(CF 2) 2SO 3H)CF 3 with from 4 to 7 explicit water molecules revealed that the perfluorocarbon backbone may adopt both an elongated geometry with all carbons in a trans configuration and also a folded conformation as a result of the hydrogen bonding of the terminal sulfonic acids with the water. Our calculations show that the fragments displaying the latter ‘kinked’ backbone possessed stronger binding of the water to the sulfonic acid groups and also effect proton dissociation with fewer water molecules. These calculations point to the importance of the flexibility of the backbone in the transport of protons for membranes with low water content.

Currents through single molecular junction of Au/hexanedithiolate/Au measured by repeated formation of break junction in STM under UHV: Effects of conformational change in an alkylene chain from gauche to trans and binding sites of thiolates on gold

The currents through single molecular bridges of 1,6-hexanedithiolate sandwiched between two gold protruded electrodes were measured by scanning tunneling microscopy (STM) under ultrahigh vacuum. The currents through the single molecules were measured by repeating formation of break junction between an Au(111) substrate covered with 1,6-hexanedithiolate and a gold STM tip, while current-separation (i-s) curves were repeatedly recorded. The gradual increase in the tunneling currents through the single molecules was observed almost every time (ca. 80%) during stretching of the molecular bridges. The increase in the tunneling currents can be attributed to the increase in the single molecular conductivity caused by the change in alkylene chains of 1,6-hexanedithiolate from gauche to trans conformations. The change from the gauche rich (4-5 gauche content in a single hexylene chain) to all-trans conformation resulted in one order of magnitude increase in the observed currents. Between the extreme gauche rich (5 gauche content) and all-trans (0 gauche content) conformations, there are many kinds of conformers (i.e., rotamers) with different gauche contents having different single molecular conductivities. Complexity of the observed currents due to such conformational changes made the study of the effect of Au-S contacts on single molecular conductivities difficult, although the effect was observed clearly for single molecular bridges with a previous rigid pi-conjugated system without the conformational effect (K. Ishizuka et al., Jpn. J. Appl. Phys., 2006, 45, 2037). To solve this problem, new methods are proposed and their usefulness is demonstrated.

On the consequences of side chain flexibility and backbone conformation on hydration and proton dissociation in perfluorosulfonic acid membranes

The flexibility of the side chain and effects of conformational changes in the backbone on hydration and proton transfer in the short-side-chain (SSC) perfluorosulfonic acid fuel cell membrane have been investigated through first principles based molecular modelling studies. Potential energy profiles determined at the B3LYP/6-31G(d,p) level in the two pendant side chain fragments: CF(3)CF(-O(CF(2))(2)SO(3)H)-(CF(2))(7)-CF(-O(CF(2))(2)SO(3)H)CF(3) indicate that the largest CF(2)-CF(2) rotational barrier along the backbone is nearly 28.9 kJ mol(-1) higher than the minimum energy staggered trans conformation. Furthermore, the calculations reveal that the stiffest portion of the side chain is near to its attachment site on the backbone, with CF-O and O-CF(2) barriers of 38.1 and 28.0 kJ mol(-1), respectively. The most flexible portion of the side chain is the carbon-sulfur bond, with a barrier of only 8.8 kJ mol(-1). Extensive searches for minimum energy structures (at the B3LYP/6-311G(d,p) level) of the same polymeric fragment with 4-7 explicit water molecules reveal that the perfluorocarbon backbone may adopt either an elongated geometry, with all carbons in a trans configuration, or a folded conformation as a result of the hydrogen bonding of the terminal sulfonic acids with the water. These electronic structure calculations show that the fragments displaying the latter 'kinked' backbone possessed stronger binding of the water to the sulfonic acid groups, and also undergo proton dissociation with fewer water molecules. The calculations point to the importance of the flexibility in both the backbone and side chains of PFSA membranes to effectively transport protons under low humidity conditions.

Mutagenesis at Pro309 of single‐chain urokinase‐type plasminogen activator alters its catalytic properties

The charge of Lys300(c143) located within a flexible loop(297-313) of sc-uPA has been identified as an important determinant for its high intrinsic activity. Mutations affecting the flexibility of the loop also modulate the intrinsic activity. Glu-plasminogen activation by sc-uPA is strongly promoted by fibrin fragment E but not fibrin fragment D-dimer, whereas plasminogen activation by t-PA is strongly promoted by fragment D-dimer but not fragment E. To further investigate the effect of conformation changes in the flexible loop on catalytic properties of sc-uPA, cassette mutations at Pro309(c152) were made and characterized. It was found that the activation of Pro309(c152) mutants by Lys-plasmin was only moderately affected. In contrast, the intrinsic and two-chain activities of Pro309(c152) mutants against S2444 were both significantly decreased. The two-chain activities of these mutants against Glu-plasminogen were also reduced in a range of 1.1- to 127-fold. The mutations of Pro309(c152) to Trp/Phe and Arg/Asp more significantly affected both intrinsic and two-chain activities, while only a moderate decrease in activity was found with mutations to Ala/Ser/Thr. In contrast to wild-type sc-uPA, plasminogen activation by Pro309(c152) mutants was found to be promoted by both fibrin fragment E and D-dimer. In the presence of 2.0 microM D-dimer, plasminogen activation by mutant Pro309(c152) --> His was promoted by 22-fold, while only 2.0-fold promotion was found with mutant Pro309(c152) --> Gly. In conclusion, these findings demonstrated that conformation changes in the flexible loop of sc-uPA not only affect its intrinsic and two-chain activity, but also extend its promotion of plasminogen activation by fragment E to D-dimer.

A conformational switch of intramolecular electron transfer

Quantum chemical calculations and experiments on model compounds are used to study the effect of conformational changes on intramolecular electron transfer in perylenebisimide–biphenyl dyads. The molecular orbital energy level of the biphenyl moiety and thus the free energy change for electron transfer depends on the dihedral angle between the two phenyl rings. Dramatic changes in the orbital energy levels result in very different electron transfer behavior for three model compounds. These changes are accurately predicted by calculations using density functional theory, which also give accurate results for geometries, suggesting such calculations can be useful in designing molecular electronic species.

A theoretical study of zero-field splitting of organic biradicals

A theoretical method for ab initio calculations of the zero-field splitting parameters from electron spin–spin interaction contributions is described. This methodology is applied to typical organic biradicals within the density-functional theory. It is shown that this approach can provide results in good agreement with experimental values for typical organic biradicals at moderate computational cost. Magnetic properties are discussed in detail for typical organic biradicals, such as carbene, vinylmethylene, phenylcarbene, and diphenylcarbene. Their spin orbitals, magnetic axes, and effects of conformational changes are investigated. Moreover, the relationship between those three factors and the zero-filed splitting parameters (D- and E) including their signs is revealed. This method has been proved to be quite valid in studying organic ferromagnets.

Some Calculations of Molecular Chirality

ABSTRACT Chirality of optically active liquid crystal molecules has become an important research topic. Different approaches, both theoretical and experimental have been undertaken to create a better understanding of the concept of chirality in liquid crystals. Surprisingly good agreement is found from predictions from single molecules for phase properties. The scaled chiral index with no solvent interaction has been successful in predicting the helical twisting power of a range of dopants in nematic solvents. We present here results for both single molecule studies and molecular dynamics simulations for two biphenyl dopants and discuss the effect of conformational change on the predictions of the scaled chiral index of helical twisting power.

Capillary condensation of short-chain molecules

A density-functional study of capillary condensation of fluids of short-chain molecules confined to slitlike pores is presented. The molecules are modeled as freely jointed tangent spherical segments with a hard core and with short-range attractive interaction between all the segments. We investigate how the critical parameters of capillary condensation of the fluid change when the pore width decreases and eventually becomes smaller than the nominal linear dimension of the single-chain molecule. We find that the dependence of critical parameters for a fluid of dimers and of tetramers on pore width is similar to that of the monomer fluid. On the other hand, for a fluid of chains consisting of a larger number of segments we observe an inversion effect. Namely, the critical temperature of capillary condensation decreases with increasing pore width for a certain interval of values of the pore width. This anomalous behavior is also influenced by the interaction between molecules and pore walls. We attribute this behavior to the effect of conformational changes of molecules upon confinement.

The temperature dependent electrical transport in biphenyl derivatives

The d.c. electrical conductivity measurements as a function of temperature of 4,4-dibromobiphenyl (DBrBP), 4,4-dichlorobiphenyl (DClBP) and 4,4-dimethoxybiphenyl (DMOBP) compounds have been carried out. The effects of conformational change within skeleton of these compounds upon optical or thermal excitation (S1 S0) and of para substituents on the electrical conductivity have been discussed. The conduction processes were interpreted in the light of their molecular spectroscopic data of the infrared, ultraviolet and emission spectra as a hopping processes. The semiconducting properties of the investigated compounds were arising from electron-delocalization via intramolecular interaction of p-electrons of (C@C) bonds and electron-donating groups in para positions. The conductivity was found to increase in the higher temperature range than in lower due to the planar structure which increases the possibility of electron-delocalization and the interaction of p-electron system. � 2005 Elsevier B.V. All rights reserved.

Effect of conformational changes on a one-electron reduction process: evidence of a one-electron P-P bond formation in a bis(phosphinine).

EPR spectra show that one-electron reduction of bis(3-phenyl-6,6-(trimethylsilyl)phosphinine-2-yl)dimethylsilane (1) on an alkali mirror leads to a radical anion that is localized on a single phosphinine ring, whereas the radical anion formed from the same reaction in the presence of cryptand or from an electron transfer with sodium naphthalenide is delocalized on the two phosphinine rings. Density functional theory (DFT) calculations show that in the last species the unpaired electron is mainly confined in a loose P-P bond (3.479 A), which results from the overlap of two phosphorus p orbitals. In contrast, as attested by X-ray spectroscopy, the P-P distance in neutral 1 is large (5.8 A). As shown by crystal structure analysis, addition of a second electron leads to the formation of a classical P-P single bond (P-P 2.389 A). Spectral modifications induced by the presence of cryptand or by a change in the reaction temperature are consistent with the formation of a tight ion pair that stabilizes the radical structure localized on a single phosphinine ring. It is suggested that the structure of this pair hinders internal rotation around the C-Si bonds and prevents 1 from adopting a conformation that shortens the intramolecular P-P distance. The ability of the phosphinine radical anion to reversibly form weak P-P bonds with neutral phosphinines in the absence of steric hindrance is confirmed by EPR spectra obtained for 2,6-bis(trimethylsilyl)-3-phenylphosphinine (2). Moreover, as shown by NMR spectroscopy, in this system, which contains only one phosphinine ring, further reduction leads to an intermolecular reaction with the formation of a classical P-P bond.

Experimental investigations and ab initio studies of selenium(ii) dialkanethiolates, Se(SR)2

Selenium(II) dimethanethiolate, Se(SMe)(2), was synthesized by reaction of SeO(2) with HSMe. Basic spectroscopic data for Se(SMe)(2) and selenium(II) bis(2-methyl-2-propanethiolate), Se(S(t)Bu)(2), were recorded and interpreted with the support of ab initio calculations. Both compounds are thermodynamically unstable relatively to selenium and the corresponding disulfide. The UV/vis spectra of both compounds are qualitatively similar, the two bands being attributed to n(Se)-sigma*(Se-S) transitions. The bands at 369 and 397 cm(-1) in the IR spectra of Se(SMe)(2) and Se(S(t)Bu)(2), respectively, are assigned to nu(as)(SeS(2)). The (77)Se NMR shifts of Se(SMe)(2)(784 ppm) and Se(S(t)Bu)(2)(556 ppm) differ substantially from each other and show positive temperature gradients. Calculations at the GIAO-HF/962+(d) level reproduced the difference of the (77)Se NMR chemical shifts between Se(SMe)(2) and Se(S(t)Bu)(2). At the same level, the effect of conformational changes on (77)Se shifts were studied for Se(SMe)(2). In the solid state Se(SMe)(2) forms long intermolecular SeS contacts while Se(S(t)Bu)(2) does not. Both compounds exhibit anti-conformations of the methyl and tert-butyl groups with respect to the SeS(2) plane. MP2/LANL2DZ(d) geometry optimizations, single point energy and frequency calculations performed for Se(SMe)(2) show, that syn- (C(s)) and anti-conformers (C(2)) represent minima on the potential energy surface, the latter being by 8 kJ mol(-1) lower in energy than the former. Both conformers are stabilized by intramolecular pi-type n(S(1))-sigma*(Se-S(2)) orbital interactions. The energy of the transition state for the mutual conversion of the two conformers was calculated to be 31 kJ mol(-1) above that of the syn conformer, allowing a rapid interconversion of the two conformers at room temperature. Intermolecular interactions between Se(SMe)(2) molecules were also studied by means of calculations at the MP2/LANL2DZ(d) level. For Se(S(t)Bu)(2) MP2/LANL2DZ(d) geometry optimizations and single point energy calculations revealed a C(2)-symmetric anti- and a C(1) symmetric syn-conformer, the latter being 21 kJ mol(-1) higher in energy than the former. Se(SMe)(2) and Se(S(t)Bu)(2) exchange thiolate groups with other selenium(II) dithiolates, tellurium(II) dithiolates and with thiols, if catalytic amounts of p-CH(3)C(6)H(4)SO(3)H are added.