Energetic Destabilization Research Articles

Energetic destabilization of shut states underpins the membrane stretch dependent activation of Piezo1.

Piezo1 is a non-selective cation channel activated by mechanical stimuli such as cell membrane stretch. It has been shown that Piezo1 conforms to a curved, upright, bowl-like structure in its non-conductive (“shut”) state. Stretching of the cell membrane is thought to flatten this curved structure of Piezo1 to open its ion-conducting pore. Yet, how stretching of the cell membrane modulates the functional states of Piezo1 to open the channel is not known. Therefore, we collected single-channel Piezo1 recordings at various steady-state pressure-induced membrane stretch to study how the membrane stretch alters functional states of Piezo1. One-dimensional single-channel dwell time histograms reveal that Piezo1 has a minimum of two shut (long-lived and short-lived) and two open (long-lived and short-lived) functional states. Two-dimensional dwell time histograms and Markov modeling show that membrane stretch increases the rate of microscopic shut-to-open transitions, with relatively smaller effects on closure rates. Critically, increasing membrane stretch up to saturation of open probability correlates with a ∼25- and ∼50-fold decrease of mean dwell times for the short-lived and long-lived shut states, respectively. In contrast, the mean dwell times for the short-lived and long-lived open states only increased by ∼3- and ∼2-fold, respectively. Taken together, these results indicate that membrane stretch predominantly acts by energetically destabilizing Piezo1 shut states.

The physical nature of the ultrashort spike-ring interaction in iron maiden molecules.

The so-called 'iron maiden' molecules belong to one of the most interesting subgroups of cyclophanes due to the presence of the ultrashort interaction between the CX apical bond and the benzene ring. This article presents an in-depth theoretical study of 16 'iron maiden' molecules, in which X=H, F, Cl or Br and the side chains are of various lengths and types: CSC, CSCC, CCC, and CCCC. It is shown that the H → F → Cl → Br substitution leads to a significant expansion of the 'iron maiden' molecule. Shorter chains lead to more pronounced effects, while insertion of sulfur atoms into the side chains lowers them. Structural changes are associated with an increase in energetic destabilization of X. Moreover, unlike for H, in the case of X=halogen, the out → in isomerization is energetically disadvantageous. The 'iron maiden' molecules are characterized by the presence of only three X⋯CAr bond paths. Particularly noteworthy are unusually large (even up to 32) values of the X⋯CAr bond ellipticity, which results from flat electron density distribution. The X⋯π interaction in each of the investigated 'iron maiden' molecule turned out to be multi-center, stabilizing and almost purely covalent in nature as indicated by the definitely dominant percentage (94.8%-101.6%) of the exchange-correlation energy. The spatial hindrance within the 'iron maiden' molecules appears to be not so much due to the X⋯π repulsion, but due to unfavorable steric interactions between X and the CC side bonds. It is also confirmed that some CH⋯HC interactions in aliphatic chains can be very weakly stabilizing.

Ligand‐to‐metal charge transfer driven by excited‐state antiaromaticity in metallohexaphyrins

AbstractWe investigated the effect of excited‐state antiaromaticity on the ligand‐to‐metal charge transfer (LMCT) process of metallohexaphyrins. According to Baird rule, the aromatic metallohexaphyrins in the S0 state become antiaromatic in the S1 state. Because of the metal–ligand redox‐like nature of LMCT process, the LMCT process can release the antiaromatic nature and its energetic destabilization. The metallohexaphyrins show a correlation between the S0‐state aromaticity and time constants for the LMCT process, which well demonstrates that the excited‐state antiaromaticity at the Franck–Condon state acts as a driving force for the LMCT process. These findings elucidate the effect of excited‐state antiaromaticity on the excited‐state behaviors and further provide an insight into the photochemistry of organic molecules.

Emerging Fluorite‐ and Wurtzite‐Type Ferroelectrics: From (Hf,Zr)O2 to AlN and Related Materials

Emerging Fluorite‐ and Wurtzite‐Type Ferroelectrics: From (Hf,Zr)O₂ to AlN and Related Materials

Upgraded molecular models of the human KCNQ1 potassium channel.

The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and various resting voltage sensor structures. Using molecular dynamics (MD) simulations, the capacity of the models to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor–pore domain interactions were validated. Rosetta energy calculations were applied to assess the utility of each model in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 experimentally characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants exhibited no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural basis for KCNQ1 function and can be used to generate hypotheses to explain KCNQ1 dysfunction.

Salvaging the Thermodynamic Destabilization of Interface Histidine in Transmembrane β-Barrels.

The ability of histidine to participate in a wide range of stabilizing polar interactions preferentially populates this residue in functionally important sites of proteins. Histidine possesses an amphiphilic and electrostatic nature that is essential for amino acids residing at membrane interfaces. However, the frequency of occurrence of histidine at membrane interfaces, particularly transmembrane β-barrels, is lower than those of other aromatic residues. Here, we carry out comprehensive energetic measurements using equilibrium folding of the outer membrane enzyme PagP to address the contribution of a C-terminal interface histidine to barrel stability. We show that placing histidine at the C-terminus universally destabilizes PagP by 4.0–8.0 kcal mol–1 irrespective of the neighboring residue. Spectroscopic and electrophoretic measurements indicate that the altered stability may arise from a loss of barrel compaction. Isoleucine, methionine, and valine salvage this destabilization marginally (in addition to tyrosine, which shows an exceptionally high folding free energy value), when placed at the penultimate position, at the expense of an altered folding pathway. Double-mutant cycle analysis indicates that the coupling energy between the terminal and penultimate residues in PagP-X160H161 increases when the level of intrinsic destabilization by the terminal H161 is high. Our observations that neighboring residues cannot salvage the energetic destabilization of histidine may explain why histidine is less abundant at membrane interfaces.

BN Doping and the Photochemistry of Polyaromatic Hydrocarbons: Photocyclization of Hexaphenyl Benzene and Hexaphenyl Borazine.

Boron-nitrogen doping of polyaromatic hydrocarbon (PAH) materials can be used to tune their electronic properties while preserving the structural characteristics of pure hydrocarbons. Many multicycle PAHs can be synthesized photochemically; in contrast, very little is known about the photochemistry of their BN-doped counterparts. We present results of fs, ns, and μs time-resolved spectroscopic studies on the photoinduced dynamics of hexaphenyl benzene and hexaphenyl borazine in order to examine how BN doping alters photochemical C-C bond formation via 6π electrocyclization as well as the stability of resulting cyclized structures. Ultrafast measurements reveal photoinduced behaviors reflecting differences in excited-state decay pathways for the two molecules, with hexaphenyl borazine relaxing from its excited state with a rate that is 2 orders of magnitude faster than that of hexaphenyl benzene (3.0 vs 428 ps). Tetraphenyl dihydrotriphenylene generated from hexaphenyl benzene is observed to reopen with a ∼2 μs lifetime controlled by entropic stabilization of the cyclized structure; in contrast, photoinduced dynamics appear to be complete within 100 ps after excitation of hexaphenyl borazine. This significant difference in photochemical dynamics is reflected in the cyclodehydrogentation yields obtained for the two reactants (25 vs 0% for hexaphenyl benzene and borazine, respectively). Quantum-chemical computations predict that BN doping gives rise to energetic destabilization and increased singlet diradical character in cyclized structures. These findings indicate that the polarized BN bonds of the borazine core adversely impact photochemical bond formation relative to analogous hydrocarbons.

Structural and energetic factors controlling the enantioselectivity of dinucleotide formation under prebiotic conditions

Recently, it has been reported that the montmorillonite-catalyzed oligomerization of activated nucleotides exhibits remarkable enantioselectivity. In the current paper we investigate the structures and intrinsic energies of homochiral and heterochiral cyclic dinucleotides by means of accurate quantum chemical calculations in gas-phase and in bulk water. The steric effect of the clay is represented with geometrical constraints. Our computations reveal that the heterochiral dimer geometries are systematically less stable than their homochiral counterparts due to steric clashes inside the sugar-phosphate ring geometry. Thus we suggest that the homochiral selectivity observed in the cyclic dinucleotide formation in confined spaces may arise from the energetic destabilization of the heterochiral ring geometries as compared to their homochiral analogues. In the present paper we provide the first model of the 3D structure of d,l cyclic dinucleotides, which until now has eluded experimental observation.

Thermochemistry of Zeolitic Imidazolate Frameworks of Varying Porosity

The first thermochemical analysis by room-temperature aqueous solution calorimetry of a series of zeolite imidazolate frameworks (ZIFs) has been completed. The enthalpies of formation of the evacuated ZIFs-ZIF-zni, ZIF-1, ZIF-4, CoZIF-4, ZIF-7, and ZIF-8-along with as-synthesized ZIF-4 (ZIF-4·DMF) and ball-milling amorphized ZIF-4 (a(m)ZIF-4) were measured with respect to dense components: metal oxide (ZnO or CoO), the corresponding imidazole linker, and N,N dimethylformamide (DMF) in the case of ZIF-4·DMF. Enthalpies of formation of ZIFs from these components at 298 K are exothermic, but the ZIFs are metastable energetically with respect to hypothetical dense components in which zinc is bonded to nitrogen rather than oxygen. These enthalpic destabilizations increase with increasing porosity and span a narrow range from 13.0 to 27.1 kJ/mol, while the molar volumes extend from 135.9 to 248.8 cm(3)/mol; thus, almost doubling the molar volume results in only a modest energetic destabilization. The experimental results are supported by DFT calculations. The series of ZIFs studied tie in with previously studied MOF-5, creating a broader trend that mirrors a similar pattern by porous inorganic oxides, zeolites, zeotypes, and mesoporous silicas. These findings suggest that no immediate thermodynamic barrier precludes the further development of highly porous materials.

Co3O4–Co2ZnO4 spinels: The case for a solid solution

In prior first-principles theoretical work we predicted a complete solid solution in the Co3O4–Co2ZnO4 system, with a negligibly small mixing enthalpy. In this work we tested this prediction on bulk, large-grained specimens across the Co3O4–Co2ZnO4 join, combining oxide melt solution calorimetry, differential scanning calorimetry, precise lattice parameter measurements, anomalous X-ray and neutron diffraction, and in situ electrical measurements. The calorimetric results confirm the presence of a solid solution at high temperatures, but with a large enthalpy of mixing that exceeds the predicted value. Because Co3O4 and Co2ZnO4 have essentially identical lattice parameters, this energetic destabilization must arise from factors other than the strain energy resulting from size mismatch. Changes in Co3+ spin states vs. temperature and zinc content are proposed to account for the positive excess enthalpy, and may also provide additional entropy to stabilize the solid solution at high temperature.

An S4-S5 Linker Residue Influences Kv2.1 Channel Gating and Inhibition by Carbon Monoxide Releasing Molecule 2 (CORM-2)

The carbon releasing molecule 2 (CORM-2) is an allosteric inhibitor of the Shaker and Kv2.1 voltage-gated ion channels. The mechanism of inhibition is common to both channels and derives mainly from an energetic destabilization of the channel's opening transition without inhibiting voltage-sensor activation, thus partially uncoupling voltage-sensor activation from channel gating. Electromechanical coupling between the voltage-sensing domain (VSD) and the pore of Kv channels has been shown to depend on specific interactions between the S4-S5 linker and the carboxyl-terminal portion of the S6 segment. Here, we show that a single glycine to valine mutation in the S4-S5 linker of the Kv2.1 channel causes a large energetic destabilization of the channel's open state. Moreover, the G317V mutation also interferes with the channel's inhibition by CORM-2, suggesting that there is a cavity at the interphase between the VSD and the pore of the channel, including the S4-S5 linker, and that it is part of the CORM-2 binding site in the channel. These data are consistent with the mechanism of channel inhibition by this compound. Supported by Instituto de Ciencia y Tecnologia del Distrito Federal, Grant PIFUTP09-262 to L.D.I.

Effects of Nonadditive Interactions on Ion Solvation at the Water/Vapor Interface: A Molecular Dynamics Study

The solvation of halide ions at the water/vapor interface is investigated by using molecular dynamics simulations with nonpolarizable molecular mechanical (MM), polarizable MM, and quantum mechanical (QM)/MM methods. The free energy profile of the ion solvation is decomposed into the energy and the entropic contributions along the ion displacement from inside to the surface of water. It is found that the surface affinity of the ion, relative to the bulk value, is determined by a subtle balance between the energetic destabilization and the entropic stabilization with the ion displacement. The amount of energetic destabilization is found to be reduced when nonadditive interactions are included, as in the polarizable MM and QM/MM models. The structure of water around the ion at the interface is also largely modified when the higher order effects are considered. For example, the induced dipole effect enhances the solvation structure around the ion at the interface significantly and thus reduces the amount of entropic stabilization at the interface, relative to in the bulk. It is found that this induced dipole effect causes the slowing in the ion-water hydrogen bond dynamics at the interface. On the other hand, the higher order induced multipole effects in the QM/MM method suppress both the excessive enhancement of the solvation structure and the slowing of the ion-water hydrogen bond dynamics at the interface. The present study demonstrates that not only the induced dipole moment but also the higher order induced multipole moments, which are neglected in standard empirical models, are essential for the correct description of the ion solvation at the water/vapor interface.

Hydrogen Molecules inside Fullerene C70: Quantum Dynamics, Energetics, Maximum Occupancy, And Comparison with C60

Recent synthesis of the endohedral complexes of C(70) and its open-cage derivative with one and two H(2) molecules has opened the path for experimental and theoretical investigations of the unique dynamic, spectroscopic, and other properties of systems with multiple hydrogen molecules confined inside a nanoscale cavity. Here we report a rigorous theoretical study of the dynamics of the coupled translational and rotational motions of H(2) molecules in C(70) and C(60), which are highly quantum mechanical. Diffusion Monte Carlo (DMC) calculations were performed for up to three para-H(2) (p-H(2)) molecules encapsulated in C(70) and for one and two p-H(2) molecules inside C(60). These calculations provide a quantitative description of the ground-state properties, energetics, and the translation-rotation (T-R) zero-point energies (ZPEs) of the nanoconfined p-H(2) molecules and of the spatial distribution of two p-H(2) molecules in the cavity of C(70). The energy of the global minimum on the intermolecular potential energy surface (PES) is negative for one and two H(2) molecules in C(70) but has a high positive value when the third H(2) is added, implying that at most two H(2) molecules can be stabilized inside C(70). By the same criterion, in the case of C(60), only the endohedral complex with one H(2) molecule is energetically stable. Our results are consistent with the fact that recently both (H(2))(n)@C(70) (n = 1, 2) and H(2)@C(60) were prepared, but not (H(2))(3)@C(70) or (H(2))(2)@C(60). The ZPE of the coupled T-R motions, from the DMC calculations, grows rapidly with the number of caged p-H(2) molecules and is a significant fraction of the well depth of the intermolecular PES, 11% in the case of p-H(2)@C(70) and 52% for (p-H(2))(2)@C(70). Consequently, the T-R ZPE represents a major component of the energetics of the encapsulated H(2) molecules. The inclusion of the ZPE nearly doubles the energy by which (p-H(2))(3)@C(70) is destabilized and increases by 66% the energetic destabilization of (p-H(2))(2)@C(60). For these reasons, the T-R ZPE has to be calculated accurately and taken into account for reliable theoretical predictions regarding the stability of the endohedral fullerene complexes with hydrogen molecules and their maximum H(2) content.

A comparative molecular dynamics study on the complexation of alkali metal cations by a poly-ethylene-glycol type podand in water and in dichloromethane

Molecular dynamics (MD) was used to study the complexation of the alkali metal cations (Li +, Na +, K +, Rb + and Cs +) by a poly-ethylene-glycol type podand with eight potential donor oxygen atoms, in water and dichloromethane. MD simulations for the free podand in water provided evidence for a solvent driven stabilizing effect of certain conformations. The complexes in water proved to be unstable as they all dissociated well within the simulation time used. In contrast, the complexes proved to be stable in the organic solvent. Analysis of the MD trajectories for the complexes in dichloromethane showed: (i) an enlargement of the podand OC–CO dihedral angles as the cation size increases; (ii) an increase of the number of strong interactions between the oxygen atoms as the cation size increases; (iii) a considerable degree of solvent penetration into the inner coordination sphere from the potassium to cesium complexes. Quantum calculations showed a higher energetic destabilization for the lithium and sodium complex forms. The results support the experimental evidence that the extraction efficiency shown by this podand (from water to dichloromethane) is higher for potassium, rubidium and cesium than for lithium or sodium.

Tuning the Photoinduced O2-Evolving Reactivity of Mn4O47+, Mn4O46+, and Mn4O3(OH)6+ Manganese−Oxo Cubane Complexes

The manganese-oxo "cubane" core complex Mn(4)O(4)L(1)(6) (1, L(1) = Ph(2)PO(2-)), a partial model of the photosynthetic water oxidation site, was shown previously to undergo photodissociation in the gas phase by releasing one phosphinate anion, an O(2) molecule, and the intact butterfly core cation (Mn(4)O(2)L(1)(5+)). Herein, we investigate the photochemistry and electronic structure of a series of manganese-oxo cubane complexes: [Mn(4)O(4)L(2)(6)] (2), 1(+)(ClO(4-)), 2(+)(ClO(4-)), and Mn(4)O(3)(OH)L(1)(6) (1H). We report the atomic structure of [Mn(4)O(4)L(2)(6)](ClO(4)), 2(+)(ClO(4-)) [L(2) = (4-MeOPh)(2)PO(2-)]. UV photoexcitation of a charge-transfer band dissociates one phosphinate, two core oxygen atoms, and the Mn(4)O(2)L(5)(+) butterfly as the dominant (or exclusive) photoreaction of all cubane derivatives in the gas phase, with relative yields: 1H >> 2 > 1 > 2(+) > 1(+). The photodissociation yield increases upon (1) reducing the core oxidation state by hydrogenation of a corner oxo (1H), (2) increasing the electron donation from the phosphinate ligand (L(2)), and (3) reducing the net charge from +1 to 0. The experimental Mn-O bond lengths and Mn-O bond strengths and the calculated ligand binding energy explain these trends in terms of weaker binding of phosphinate L(2) versus L(1) by 14.7 kcal/mol and stronger Mn-(mu(3)-O)(core) bonds in the oxidized complexes 2(+) and 1(+) versus 2 and 1. The calculated electronic structure accounts for these trends in terms of the binding energy and antibonding Mn-O(core) and Mn-O'(ligand) character of the degenerate highest occupied molecular orbital (HOMO), including (1) energetic destabilization of the HOMO of 2 relative to 1 by 0.75 eV and (2) depopulation of the antibonding HOMO and increased ionic binding in 1(+) and 2(+) versus 1 and 2.

Single-crystal X-ray diffraction study of cation distribution in MgAl 2 O 4 ?MgFe 2 O 4 spinel solid solution

Synthesis experiments in the system MgAl2O4–MgFe2O4 [MgAl2− x Fe x O4 (0 ≤ x ≤ 2)] were carried out using a PbF2 flux. The crystalline products synthesized in the compositional range of 0.6 <x ≤ 1.2 consisted of two spinel phases, whereas those synthesized in the compositional ranges of 0.0 ≤ x ≤ 0.6 and 1.2 < x ≤ 2.0 crystallized as single spinel phases. Structure refinements of the spinel single crystals, which grew in the ranges of 0.0 ≤ x ≤ 0.6 and 1.2 < x ≤ 2.0, show that the degree of randomness of cation distribution between A and B sites increases as x approaches the two-phase region. This means that the degree of the size mismatch among Mg2+, Fe3+ and Al3+occupying each equivalent mixing site increases as x approaches the two-phase region. Consequently, if the coexistence of two spinels observed in the intermediate compositions reveals the existence of a miscibility gap at low temperatures, this increase in the degree of the size mismatch among the three cations is suggested as a factor of energetic destabilization to form the miscibility gap.

Thermal and Thermodynamic Properties of Duplex DNA Containing Site-specific Interstrand Cross-link of Antitumor Cisplatin or Its Clinically Ineffective Trans Isomer

The effect of the single, site-specific interstrand cross-link formed by cisplatin or transplatin on the thermal stability and energetics of a 20-base pair DNA duplex is reported. The cross-linked or unplatinated 20-base pair duplexes were investigated with the aid of differential scanning calorimetry, temperature-dependent UV absorption, and circular dichroism. The cross-link of both platinum isomers increases the thermal stability of the modified duplexes by changing the molecularity of denaturation. The structural perturbation resulting from the interstrand cross-link of cisplatin increases entropy of the duplex and in this way entropically stabilizes the duplex. This entropic cross-link-induced stabilization of the duplex is partially but not completely compensated by the enthalpic destabilization of the duplex. The net result of these enthalpic and entropic effects is that the structural perturbation resulting from the formation of the interstrand cross-link by cisplatin induces a decrease in duplex thermodynamic stability, with this destabilization being enthalpic in origin. By contrast, the interstrand cross-link of transplatin is enthalpically almost neutral with the cross-link-induced destabilization entirely entropic in origin. These differences are consistent with distinct conformational distortions induced by the interstrand cross-links of the two isomers. Importantly, for the duplex cross-linked by cisplatin relative to that cross-linked by transplatin, the compensating enthalpic and entropic effects almost completely offset the difference in cross-link-induced energetic destabilization. It has been proposed that the results of the present work further support the view that the impact of the interstrand cross-links of cisplatin and transplatin on DNA is different for each and might also be associated with the distinctly different antitumor effects of these platinum compounds.

Quantum Monte Carlo investigation of small He4 clusters with a He3 impurity

Small helium (4He) clusters containing the lighter isotope He3 are studied by means of quantum Monte Carlo methods. Accurate ground state energies and structural properties are obtained using accurate trial wave functions and the Tang–Tonnies–Yiu (TTY) helium–helium pair potential. The dimer He4–3He is not bound; as well as the trimer He4He23. The smallest cluster containing He3 is He24He3 with a nonrigid structure having a marked linear contribution. Interestingly, this weakly bound system, with an energy one order of magnitude less than the He34 trimer, is able to bind another He3 atom, forming the tetramer He24He23, which shows the odd feature of having five out of six unbound pairs. In general, the substitution of a single He4 atom in a pure cluster with a He3 atom leads to an energetic destabilization, as the pair He4–3He is not bound. The isotopic impurity is found to perturb only weakly the distributions of the remaining He4 atoms, which retain the high floppiness already found in the pure clusters. As the number of atoms increases the isotopic impurity has the marked tendency to stay on the surface of the cluster. This behavior is consistent with the formation of the so-called “Andreev states” of a single He3 in liquid He4 helium and droplets, where the impurity tends to form single-particle states on the surface of the pure He4.

The Role of a Conserved Proline Residue in Mediating Conformational Changes Associated with Voltage Gating of Cx32 Gap Junctions

We have explored the role of a proline residue located at position 87 in the second transmembrane segment (TM2) of gap junctions in the mechanism of voltage-dependent gating of connexin32 (Cx32). Substitution of this proline (denoted Cx32P87) with residues G, A, or V affects channel function in a progressive manner consistent with the expectation that a proline kink (PK) motif exists in the second transmembrane segment (TM2) of this connexin. Mutations of the preceding threonine residue T86 to S, A, C, V, N, or L shift the conductance-voltage relation of wild-type Cx32, such that the mutated channels close at smaller transjunctional voltages. The observed shift in voltage dependence is consistent with a reduction in the open probability of the mutant hemichannels at a transjunctional voltage ( V j) of 0 mV. In both cases in which kinetics were examined, the time constants for reaching steady state were faster for T86N and T86A than for wild type at comparable voltages, suggesting that the T86 mutations cause the energetic destabilization of the open state relative to the other states of the channel protein. The structural underpinnings of the observed effects were explored with Monte Carlo simulations. The conformational space of TM2 helices was found to differ for the T86A, V, N, and L mutants, which produce a less bent helix (∼20° bend angle) compared to the wild type, which has a ∼37° bend angle. The greater bend angle of the wild-type helix reflects the propensity of the T86 residue to hydrogen bond with the backbone carbonyl of amino acid residue I82. The relative differences in propensity for hydrogen bonding of the mutants relative to the wild-type threonine residue in the constructs we studied (T86A, V, N, L, S, and C) correlate with the shift in the conductance-voltage relation observed for T86 mutations. The data are consistent with a structural model in which the open conformation of the Cx32 channel corresponds to a more bent TM2 helix, and the closed conformation corresponds to a less bent helix. We propose that the modulation of the hydrogen-bonding potential of the T86 residue alters the bend angle of the PK motif and mediates conformational changes between open and closed channel states.

On the Role of the Pauli Antisymmetry Principle in Pericyclic Reactions

Abstract In the present work we discuss the role of the Pauli antisymmetry principle (PAP) in synchronous pericyclic reactions. These reactions are allowed in the electronic ground state whenever the PAP does not act as a quantum constraint in the transition state. The possible suppression of the influence of the PAP is a peculiarity of π electron systems. The PAP is a hidden (= deactivated) variable in the π electron subspace of polyenes and (4n + 2) annulenes (n = 0, 1, 2,...). In 4n annulenes (n = 1, 2, 3,...) it leads to minority signs in the kinetic hopping matrix of the π electronic wave function and thus to an energetic destabilization. The quantum statistical difference between the above families of π systems renders possible a microscopical definition of the quantities “aromaticity” and “antiaromaticity”. The sign behaviour of the kinetic hopping elements is used in the discussion of pericyclic reactions. The present quantum statistical description of these reactions is related to the Dewar-Zimmermann and Woodward-Hoffmann rules.