Perpendicular Conformation Research Articles

Aromatic Residues in Proteins: Re-Evaluating the Geometry and Energetics of π-π, Cation-π, and CH-π Interactions.

Aromatic residues can participate in various biomolecular interactions, such as π-π, cation-π, and CH-π interactions, which are essential for protein structure and function. Here, we re-evaluate the geometry and energetics of these interactions using quantum mechanical (QM) calculations, focusing on pairwise interactions involving the aromatic amino acids Phe, Tyr, and Trp and the cationic amino acids Arg and Lys. Our findings reveal that π-π interactions, while energetically favorable, are less abundant in structured proteins than commonly assumed and are often overshadowed by previously underappreciated, yet prevalent, CH-π interactions. Cation-π interactions, particularly those involving Arg, show strong binding energies and a specific geometric preference toward stacked conformations, despite the global QM minimum, suggesting that a rather perpendicular T-shape conformation should be more favorable. Our results support a more nuanced understanding of protein stabilization via interactions involving aromatic residues. On the one hand, our results challenge the traditional emphasis on π-π interactions in structured proteins by showing that CH-π and cation-π interactions contribute significantly to their structure. On the other hand, π-π interactions appear to be key stabilizers in solvated regions and thus may be particularly important to the stabilization of intrinsically disordered proteins.

Electronic spectra of jet-cooled 1,4-bis(phenylethynyl)benzene: Strength in π-electron conjugation and two large-amplitude torsional motions.

To spectroscopically qualify strength in the π-electron conjugation, the electronic spectra of jet-cooled 1,4-bis(phenylethynyl)benzene (BPEB) in the region of the transition to the lowest excited singlet (S1) 1B1u state are measured by the fluorescence excitation and the single-vibronic-level dispersed fluorescence methods. Strength is defined as the difference in potential energies between the planar and perpendicular conformations. BPEB possesses two large-amplitude torsional motions, out-of-phase 24 and in-phase 29 modes. The most stable is the planar conformation, and barrier heights at the perpendicular conformation are coincident in torsional potentials for the two modes. Torsional levels are successively observed up to 19± and 16- quantum levels in the ground state, respectively. Strength is determined to be 293cm-1 (3.51 kJmol-1) with an accuracy of an error range smaller than 1cm-1. In the excited state, strength is estimated to be 1549 ± 73cm-1. Combination levels of two torsional modes are also measured up to high quantum levels. A systematic decrease in frequencies is observed with increasing the quantum number. Quantum-chemistry calculations of B3LYP, CAM-B3PLYP, WB97XD, and M062X with basis sets of aug-cc-pVDZ are performed, where B3LYP theories are carried out with the dispersion correlation. The calculated strength is 1.1-2.1 times larger than observed.

Ultrafast Raman observation of the perpendicular intermediate phantom state of stilbene photoisomerization.

Trans-cis photoisomerization is generally described by a model in which the reaction proceeds via a common intermediate having a perpendicular conformation around the rotating bond, irrespective of from which isomer the reaction starts. Nevertheless, such an intermediate has yet to be identified unambiguously, and it is often called the 'phantom' state. Here we present the structural identification of the common, perpendicular intermediate of stilbene photoisomerization using ultrafast Raman spectroscopy. Our results reveal ultrafast birth and decay of an identical, short-lived transient that exhibits a vibrational signature characteristic of the perpendicular state upon photoexcitation of the trans and cis forms. In combination with ab initio molecular dynamics simulations, it is shown that the photoexcited trans and cis forms are funnelled off to the ground state through the same, perpendicular intermediate.

Spirobifluorene-fused strategy enables pure-green multiple resonance emitters with low efficiency roll-off.

Herein, we present a molecular design strategy centered on the spiroannulation of the MR-core skeleton to fabricate green MR-emitters and reduce device efficiency roll-off. Fusing 9,9'-spirobifluorene into the central framework of MR-emitters facilitates the distribution of the highest occupied molecular orbital (HOMO) across the spiro units, leading to a red-shifted emission and giving rise to a pure-green MR-emitter (DPhCz-SFBN) with the Commission Internationale de l'Eclairage (CIE) coordinates of [0.16, 0.74] in toluene solution, closely matching the BT.2020 standard for green. Additionally, the resultant highly twisted hetero[6]helicene conformation and a nearly perpendicular conformation of spirocycle structure effectively minimize close π-π stacking interactions among the MR-emitting cores, thereby reducing exciton quenching. Consequently, organic light-emitting diodes (OLEDs) based on DPhCz-SFBN exhibit a high maximum quantum efficiency (EQEmax) of 32.8% with low efficiency roll-off, maintaining an EQE of 23.2% at a practical luminance level of 5000 cd m-2.

When Phenyl and Cyclopropyl Rings Meet: Spectroscopic Shifts and Conformational Questions.

The electronic and vibrational spectra of cyclopropylbenzene (CPB) and 1,3-bromocyclopropylbenzene (BrCPB) in the gas phase were investigated using quantum chemical calculations in combination with resonance-enhanced multi-photon ionization REMPI techniques including 1c-R2PI, UV-UV holeburning, and IR-UV ion depletion in the CH stretch region. The electronic spectra revealed the presence of a single conformer for both species, with the absence of any perpendicular conformer attributed to low computed barriers to conformer interconversion. Assignment of CPB to the bisected conformer was made through interpreting distinctive CH stretch bands in the IR-UV spectrum in conjunction with quantum chemical calculations. A local anharmonic model based on DFT calculations was adapted to reproduce the cyclopropyl CH stretch spectrum successfully. It was not feasible to definitively assign which bisected conformer of BrCPB was observed using vibrational information alone due to the close similarity of their predicted IR spectra. However, conformational sensitivity of the S1 ← S0 transition dipole moment (TDM) alignments leads to simulated rotational contours that display stark differences, which prompted assignment to the "B1" bisecting conformer with the cyclopropyl ring directed away from the bromine atom. The absence of the energetically comparable "B2" conformer is unexpected. The analysis of the convolution of aromatic and aliphatic modes serves as a basis for assignment in constrained aliphatic systems.

Theoretical studies on thermally activated delayed fluorescence of "carbene-metal-amide" Cu and Au complexes: geometric structures, excitation characters, and mechanisms.

"Carbene-metal(I)-amide" (CMA) complexes have garnered significant attention due to their remarkable properties and potential TADF applications in organic electronics. However, the atomistic working mechanism is still elusive. Herein, we chose two CMA complexes, i.e., cyclic (alkyl)(amino) carbene-copper[gold](I)-carbazole (CAAC-Cu[Au]-Cz), and employed both DFT and TD-DFT methods, in combination with radiative and nonradiative rate calculations, to investigate geometric and electronic structures of these two complexes in the ground and excited states, including orbital compositions, electronic transitions, absorption and emission spectra, and the luminescence mechanism. It is found that the coplanar or perpendicular conformations are coexistent in the ground state (S0), the lowest excited singlet state (S1), and the triplet state (T1). Both the coplanar and perpendicular S1 and T1 states have similar ligand-to-ligand charge transfer (LLCT) character between CAAC and Cz, and some charge-transfer character between metal atoms and ligands, which is beneficial to minimize the singlet-triplet energy gaps (ΔEST) and increase the spin-orbit coupling (SOC). An interesting three-state (S0, S1, T1) model involving two regions (coplanar and perpendicular) is proposed to rationalize the experimental TADF phenomena in the CMA complexes. In addition to the coplanar ones, the perpendicular S1 and T1 states also play a role in promoting the repopulation of the coplanar S1 exciton, which is a primary source for the delayed fluorescence.

BINOL-like atropisomeric chiral nanographene.

Interest in making chiral polycyclic aromatic hydrocarbons (PAHs) or nanographenes (NGs) has greatly increased recently. To date, a majority of chiral nanocarbons have been designed based on helical chirality. Here, we describe a novel atropisomeric chiral oxa-NG 1 by the selective dimerization of naphthalene-containing, hexa-peri-hexabenzocoronene (HBC)-based PAH 6. The photophysical properties of the oxa-NG 1 and monomer 6 were investigated, including UV-vis absorption (λ max = 358 nm for 1 and 6), fluorescence emission (λ em = 475 nm for 1 and 6), fluorescence decay (15 vs. 16 ns), and fluorescence quantum yield, and it was found that the photophysical properties of the monomer are nearly maintained in the NG dimer due to its perpendicular conformation. Single-crystal X-ray diffraction analysis shows that both enantiomers cocrystallize in a single crystal, and the racemic mixture can be resolved by chiral high-performance liquid chromatography (HPLC). The circular dichroism (CD) spectra and circularly polarized luminescence (CPL) of the enantiomers of 1-S and 1-R were studied and the CD and CPL spectra exhibited opposite Cotton effects and fluorescence signals. Density functional theory (DFT) calculations and HPLC-based thermal isomerization results showed that the racemic barrier is as high as 35 kcal mol-1, suggesting a rigid chiral nanographene structure. Meanwhile, in vitro studies indicated that oxa-NG 1 is an efficient photosensitizer for white-light-induced singlet oxygen generation.

How cyclodextrin encapsulation improves molecular stability of apple polyphenols phloretin, phlorizin, and ferulic acid: Atomistic insights through structural chemistry

Phloretin (PRT), phlorizin (PRZ), and ferulic acid (FEA) prevalent in apples are unstable and less soluble in water, which can be improved by cyclodextrin (CD) encapsulation. This study aimed to provide atomistic insights of β-CD–PRT (1), β-CD–PRZ (2), and α-CD–FEA (3) complexes. Single-crystal X-ray diffraction (XRD) revealed that one PRZ (2) and one FEA (3) insert the aromatic B-ring and C=C–C=O(O) group respectively into the β-CD (2) and α-CD (3) cavities, whereas a half-occupied PRT (1) inserts the B-ring across the β-CD cavity. The induced-fit process yielded thermodynamically stable complexes 2 > 1 > 3, in agreement with the density functional theory (DFT)-optimized structures with the corresponding number of intermolecular OH···O H-bonds (7 > 3 > 1). Perpendicular conformations of the pharmaceutically active forms of PRT (1) and PRZ (2) are first observed crystallographically. This study confirmed the potential applications of CDs as molecular stabilizers and aqueous solubilizers for the improved bioavailability and efficient delivery of food bioactive compounds.

Solvent-dependent dual emission processes in charge-transfer excited states of phenothiazine-triphenyltriazine conformers

The solvent effects were studied on charge-transfer excited states in a donor–acceptor-type luminescent material, phenothiazine-triphenyltriazine, which has two distinct conformers: quasi-coplanar and perpendicular conformers. The solvent dielectric permittivity dependence of the steady-state photoluminescence spectra using solvent mixtures of toluene and tetrahydrofuran (THF) indicated that the two conformers have nearly identical excited-state dipole moments. The time-resolved photoluminescence and transient absorption spectra in toluene and THF showed different solvent dependences for the two conformers. A detailed analysis of these time-resolved spectra revealed solvent-dependent emission processes in the two conformers.

Multiple yet switchable hydrogen-bonded organic frameworks with white-light emission

The development of new strategies to construct on-demand porous lattice frameworks from simple motifs is desirable. However, mitigating complexity while combing multiplicity and reversibility in the porous architectures is a challenging task. Herein, based on the synergy of dynamic intermolecular interactions and flexible molecular conformation of a simple cyano-modified tetraphenylethylene tecton, eleven kinetic-stable hydrogen-bonded organic frameworks (HOFs) with various shapes and two thermo-stable non-porous structures with rare perpendicular conformation are obtained. Multimode reversible structural transformations along with visible fluorescence output between porous and non-porous or between different porous forms is realized under different external stimuli. Furthermore, the collaborative of flexible framework and soft long-chain guests facilitate the relaxation from intrinsic blue emission to yellow emission in the excited state, which represents a strategy for generating white-light emission. The dynamic intermolecular interactions, facilitated by flexible molecular conformation and soft guests, diversifies the strategies of construction of versatile smart molecular frameworks.

Stereochemical control of the diphosphine and alkyne ligands in triruthenium clusters: The effect of reversible CO loss/addition on the ligand distribution in [Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)7,8

Thermolysis of [Ru3{µ-Ph2PCH(Me)PPh2}(CO)10] (1) in the presence of diphenylacetylene affords the corresponding alkyne-substituted cluster [Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)8] (2) and its unsaturated counterpart [Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)7] (3), along with the alkyne-coupled complexes [Ru3{κ2-Ph2PCH(Me)PPh2}{µ3,η4-(CPh)4}(CO)4(µ-CO)2] (4) and [Ru2{µ-Ph2PCH(Me)PPh2}{µ,η4-(CPh)4}(CO)4] (5). The backbone-modified diphosphine in 2 has facilitated the growth of single crystals of the same and whose molecular structure was established by X-ray crystallography. The Ph2PCH(Me)PPh2 ligand bridges two ruthenium centers and occupies adjacent axial sites at one of the metallic faces. The diphosphine is situated trans to the alkyne ligand that caps the opposite metallic face. X-ray structural analysis of 3 reveals a perpendicular conformation of the alkyne relative to the metal triangle and a bridging diphosphine that coordinates the adjacent equatorial sites of the alkyne-bisected Ru–Ru bond. The kinetics for the conversion of 2 → 3 + CO under argon have been investigated over the temperature range 298–343 K in toluene. The calculated activation parameters [ΔHǂ = 13.3(3) kcal/mol; ΔSǂ = − 31(1) eu] are inconsistent with a rate-limiting step involving a dissociative loss of CO. Consistent with earlier reports on the related analog [Ru3(µ3,η2-PhCCPh)(µ-Ph2PCH2PPh2)(CO)7] by Lavigne and coworkers, the addition of CO to 3 (1 atm CO) at 258 K is rapid and affords 2 with a rate constant of 1.12(2) e−1s−1. Cluster 3 exhibits high reactivity toward 2e donors. Control experiments confirm that 3 reacts with additional PhCCPh (66 °C, 1 h) to give the diruthenium derivative 5 and that 4 also gives 5 in refluxing THF. The reaction of 3 with hydrogen gas (1 atm, 25 °C, 20 min) yields the dihydride [H2Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)7] (6) in 85% yield. Clusters 2−6 were characterized by IR, 1H, and 31P NMR spectroscopies, and the solid-state structures of 2−5 were established by single-crystal X-ray crystallography. The bonding in clusters 2 and 3 and the thermodynamics for the equilibrium involving 2 ⇆ 3 + CO have been evaluated by electronic structure calculations.

Electronic properties and reactivity of oxidized graphene nanoribbons and their interaction with phenol.

The effect of the oxidized functional groups on the structural, electronic, and reactivity properties of armchair graphene nanoribbons has been investigated in the framework of the density functional theory. The presence of functional groups near the edges stabilizes the oxidized graphene nanoribbons (OGNRs) more than substituting near the center. Overall, we found slight differences in the electronic properties of OGNRs concerning the pristine ones. The oxygen contribution of functional groups to the DOS is found in the conducting energy bands far from the Fermi level. Consequently, the semiconducting behavior is maintained after doping. Based on the reactivity of OGNRs, the most promising nanostructures were proposed as adsorbents studying the interaction and complexation with phenol, a critical pollutant removed mainly by hydrotreating processes (HDO) to produce bio-oil. Parallel and perpendicular phenol conformations were found towards the OGNRs in the optimized complexes driven by a physisorption process. These results provide significant insights for catalytic processes that use biomass derivatives containing phenolic compounds. The physisorption of streams containing pollutants on OGNRs could be adapted to new technological applications for the remotion of aromatic compounds under environmentally friendly operational conditions.

Exploring Curious Covalent Bonding: Raman Identification and Thermodynamics of Perpendicular and Parallel Pancake Bonding (Pimers) of Ethyl Viologen Radical Cation Dimers.

Viologen radical cations can dimerize in solutions, and the resulting "pimers" were predicted to assemble into parallel and perpendicular conformers by density functional theory (DFT) calculations. Using resonance Raman, we could identify both perpendicular and parallel forms of ethyl viologen dimers. The distinction between the two forms was accomplished by studying the formation of a host-guest complex with γ-cyclodextrin. The dimer's perpendicular form was excluded due to the host cavity size, and γ-cyclodextrin addition caused a decrease in peak intensities at 1171, 1511, and 1602 cm-1 that could be assigned to the perpendicular form. DFT modeling of the vibrational spectra under preresonance conditions allowed us to assign the remaining vibrational modes for the parallel and perpendicular forms. Using variable-temperature UV-vis, the bond dissociation energy (ΔH) for this pancake-bonded dimer was measured as 13.1 ± 0.2 kcal/mol. This type of covalent pancake bonding is a challenge to properly describe using DFT methods. Previously, B97D was found to best describe the ΔG of this dimerization (Angew. Chem. 2017, 129, 9563-9567), but this method underestimates the ΔH by 6 kcal/mol. Of the 11 functionals tested, we found that B3LYP with Grimme's D3 dispersion effect can best reproduce the ΔH. Energy decomposition analysis of the bonding energy showed that solvation effects were the most important contributor-polar solvents are needed to overcome the Coulomb repulsion between the two positively charged monomers. Dispersion effects are second in importance and appear larger than the favorable orbital interaction obtained by singly occupied molecular orbital (SOMO)-SOMO orbital overlap. This study brings forth important insights into the curious cases of covalent bonding between two π-delocalized radicals.

Selective dissociation of benzoic acid on carbonate surfaces: A density functional theory perspective

The adsorption of benzoic acid (BA) and the consequent benzoate (B) formation are fundamental processes responsible for wettability alteration on carbonate surfaces in the carbonate-oil interface. However, mixed wettability due to the occurrence of both Ca2+ and Mg2+ ions leads to current not well-understood changes in chemical properties related to BA and B formation. Therefore, we investigated by Density-Functional Theory a dissociative adsorption mechanism through different parallel and perpendicular conformations of BA and B on the calcite and dolomite (101-4) surfaces. In particular, BA is stably adsorbed on both carbonate surfaces main due to charge distribution between the carboxyl group and the surface cations. Furthermore, we find that the hydroxyl group tends to be available on dolomite rather than on calcite, being experimentally supported as the source for the possible BA selective adsorption. The calculated dissociation energy barrier also shows that dolomite surface displays the ideal condition just for a possible kinetic dependence upon the presence of water molecules. Therefore, we concluded that the mixture of calcite and dolomite portions in the reservoir surface could indeed work together upon the B formation. Accordingly, our results provide fundamental insights for the dissociation of acid oil components on mixed carbonate surfaces.

The self-assembly and microscopic interfacial properties of a supercritical CO2 microemulsion having hydrotropes: Atom-level observation from molecular dynamics simulation

Supercritical carbon dioxide microemulsion is a complex fluid mixture with distinct nano-scale microstructure that can be tailored to synthesize nano-particles and conduct interfacial reactions, which generally forms under high pressure. Reducing the pressure needed is significantly valuable for promoting the accessibility of the scCO2 microemulsion technology and further spurring the development of CO2-based green chemistry or chemical process. In this paper, we provide the direct evidence for the formation of 4FG(EO)2 based water in scCO2 microemulsion and study the microscopic mechanism of the positive synergistic effect of a series of sodium p-alkyl benzoate (hydrotrope) using molecular dynamics simulation method. Results show that the three additives can be effectively solubilized into the microemulsion aggregate and mainly distribute at the water-CO2 interface. Conformational analysis shows that sodium benzoate (BA0) stands at the interface with a relatively perpendicular conformation, while sodium p-ethyl benzoate (BA2) and sodium p-octyl benzoate (BA8) tend to lie on the interface by side. The packing of the surfactant molecules and interaction energy within the interfacial region are examined to reveal the specific microscopic origin of the positive synergistic effect between different hydrotropes and the surfactant in the sense of contributing to the stability of the aggregate, which is favorable for lowering the pressure needed to construct scCO2 microemulsion. This work is expected to direct the better design of the surfactant and rational choice of additives to successfully construct scCO2 microemulsion under lower pressure or even surfactant-free scCO2 microemulsion, which facilitates the application of scCO2 meeting industrial requirements.

Rapid relaxation pathway of the excited state of linear merocyanines in solutions

AbstractExcited‐state relaxation of linear merocyanine dyes in solution is investigated using time‐resolved spectroscopy techniques and quantum chemical calculations. The merocyanine L‐Mero4 and phenyl‐substituted P‐L‐Mero4 have a S‐trans and S‐cis structure, respectively, consisting of indole moiety as the donor, indandione as the acceptor, and the tetramethine as the bridge. The time‐correlated single‐photon counting (TCSPC) picosecond measurements after excitation at wavelength 515 nm to the ππ* state yield emission curves with a short component τ1 in the range of 27–160 ps and a second component τ2 of 200–780 ps for L‐Mero4. In P‐L‐Mero4, τ1 lies in the range of 18–150 ps and τ2 220–520 ps. The subfemtosecond transient absorption measurements yield a short component around 0.4–1.4 ps, and the second/third components are similar to those in the TCPSC measurements. The analysis of the experimental data demonstrates that the ground state recovery exhibits a biexponential rise and rapidly indicates that the conversion back to the electronic ground state provides a fast, nonradiative pathway. Quantum chemical calculations on the electronic structures and their dependence on the molecular confirmation are performed. We identify the excited states and the relaxation path along the twist of the center double bonds in tetramethine that might be the nonradiative pathway. The C=C double bond is weakened in the ππ* state. The phenyl substitution in the conjugated double bond weakens this C=C bond, lowers the isomerization barrier, increases the nonradiative rate, and reduces the emission quantum yield. In polar solvents, the energy of the perpendicular conformer along the trans–cis isomerization path is increased to achieve less coupling to the ground state surface. Because of the small barrier to the trans form, these two conformers establish an equilibrium condition. The trans form, which lies at a lower energy, gains more population and thus has a higher emission yield.

Time-Resolved Photochemistry of Stiffened Stilbenes.

Broadband transient absorption spectroscopy is used to study the photoisomerization of stiffened stilbenes in solution, specifically E/ Z mixtures of bis(benzocyclobutylidene) (t4, c4) and ( E)-1-(2,2-dimethyltetralinylidene)-2-2-dimethyltetraline (t6). Upon excitation to S1, all evolve to perpendicular molecular conformation P, followed by decay to S0, while the spectra and the kinetic behavior crucially depend on the size of the stiffening ring. In 4, contrary to all previously studied stilbenes, the trans and cis absorption and excited-state spectra are nearly indistinguishable, while the corresponding isomerization times are comparable: τi = 166 ps for t4 and τi = 64 ps for c4 in n-hexane, as opposed to 114 and 45 ps in acetonitrile, respectively. Faster isomerization in polar solvents agrees with the zwitterionic character of the P state. In t6, torsion to P is effectively barrier-less and completes within 0.3 ps, the S1 → P evolution being directly traceable through the transient spectra of stimulated emission and that of excited-state absorption. In n-hexane, the P state is remarkably long-lived, τP = 1840 ps, but the lifetime drops down to 35 ps in acetonitrile. The trans-to-cis photoisomerization yield for t6 is measured to be 20%, while for t4, it remains uncertain. We discuss the effects of stiffening and substitution on the formation and lifetime of the intermediate states through which the stilbene molecules evolve on the S1 energy surface.

Synthesis and Conformational Analysis of 10-Mesitylanthracene-1,8-diyl Oligomers

Oligomers consisting of 10-mesitylanthracene-1,8-diyl units were synthesized by Ni-mediated coupling of the corresponding dibromide as new oligoarene compounds. The structures and properties of these oligomers were investigated by NMR and electronic spectroscopy. Conformational analyses with the aid of DFT calculations revealed that each biaryl axis adopted a nearly perpendicular conformation, and the trimers and tetramers existed as a mixture of diastereomeric conformers.

Glycerol Solvates DPPC Headgroups and Localizes in the Interfacial Regions of Model Pulmonary Interfaces Altering Bilayer Structure

The inclusion of glycerol in formulations for pulmonary drug delivery may affect the bioavailability of inhaled steroids by retarding their transport across the lung epithelium. The aim of this study was to evaluate whether the molecular interactions of glycerol with model pulmonary interfaces provide a biophysical basis for glycerol modifying inhaled drug transport. Dipalmitoylphosphatidylcholine (DPPC) monolayers and liposomes were used as model pulmonary interfaces, in order to examine the effects of bulk glycerol (0-30% w/w) on their structures and dynamics using complementary biophysical measurements and molecular dynamics (MD) simulations. Glycerol was found to preferentially interact with the carbonyl groups in the interfacial region of DPPC and with phosphate and choline in the headgroup, thus causing an increase in the size of the headgroup solvation shell, as evidenced by an expansion of DPPC monolayers (molecular area increased from 52 to 68 Å2) and bilayers seen in both Langmuir isotherms and MD simulations. Both small angle neutron scattering and MD simulations indicated a reduction in gel phase DPPC bilayer thickness by ∼3 Å in 30% w/w glycerol, a phenomenon consistent with the observation from FTIR data, that glycerol caused the lipid headgroup to remain oriented parallel to the membrane plane in contrast to its more perpendicular conformation adopted in pure water. Furthermore, FTIR measurements suggested that the terminal methyl groups of the DPPC acyl chains were constrained in the presence of glycerol. This observation is supported by MD simulations, which predict bridging between adjacent DPPC headgroups by glycerol as a possible source of its putative membrane stiffening effect. Collectively, these data indicate that glycerol preferentially solvates DPPC headgroups and localizes in specific areas of the interfacial region, resulting in structural changes to DPPC bilayers which may influence cell permeability to drugs.

Choreography of the Reductase and P450BM3 Domains Toward Electron Transfer Is Instigated by the Substrate.

The driving force for the electron transfer (ET) step in the catalytic cycle of cytochrome P450BM3 is investigated using three sets of 1 μs molecular dynamic simulations for the resting state of P450 in complex with the flavin (FMN) in the reductase domain. These sets involve the following: (i) substrate-free (SF), (ii) substrate (N-palmitoyl glycine, i.e., NPG)-bound (SB), and (iii) SB with the semiquinone radical anion (SQ-) of FMN. Starting from the X-ray structure of the SF heme domain, we observe that the α1-helix (of the reductase) and the C-helix (of the heme) undergo reorientation to a parallel orientation, which is the thermochemically stable form. The reorientation of the helices pushes away the FMN to a distance of 18.4 Å from the heme's center. When the substrate binds it causes the I-helix of the heme domain to kink and push the C-helix toward the α1-helix, thereby locking the latter two into a stabilized perpendicular conformation, wherein the FMN-heme distance is 12 Å. The distance drops further in the SQ- form, and upon QM/MM geometry optimization the two moieties approach 8.8 Å, which enhances the ET rate (by 104-106 fold) to the heme's Fe3+ ion. These motions are driven by hydrogen bond strengthening between the C- and the α1-helices. Finally, substrate binding leads to formation of an organized water chain connecting the FMN and heme moieties. The water channel assists the ET and couples it to the proton transfer steps that should activate O2 and create the oxo-iron active species.