Ultrafast structural changes direct the first molecular events of vision.

Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs)1. A photon is absorbed by the 11-cis retinal chromophore of rhodopsin, which isomerizes within 200 femtoseconds to the all-trans conformation2, thereby initiating the cellular signal transduction processes that ultimately lead to vision. However, the intramolecular mechanism by which the photoactivated retinal induces the activation events inside rhodopsin remains experimentally unclear. Here we use ultrafast time-resolved crystallography at room temperature3 to determine how an isomerized twisted all-trans retinal stores the photon energy that is required to initiate the protein conformational changes associated with the formation of the G protein-binding signalling state. The distorted retinal at a 1-ps time delay after photoactivation has pulled away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Notably, the very early structural motions in the protein side chains of rhodopsin appear in regions that are involved in later stages of the conserved class A GPCR activation mechanism. Our study sheds light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of agonist-mediated GPCR activation.

Air and Water Stable Bicyclic (alkyl)(amino)Carbene Stabilized Phosphenium Cation: Reactivity and Selective Fluoride Ion Affinity.

The synthesis and reactivity of an air and water stable Bicyclic (alkyl)(amino)carbene (BICAAC) stabilized phosphenium cation (1) is reported. Air and water stable phosphenium cation are rare in the literature. Compound 1 is obtained by reaction of BICAAC with Ph2PCl in THF followed by anion exchange with LiOTf. The reduction and oxidation of 1 yielded corresponding α-radical phosphine species (2) and BICAAC stabilized phosphenium oxide (3) respectively. All compounds are well characterized by single crystal X-ray diffraction studies. The Lewis acidity of compounds 1 and 3 are determined by conducting fluoride ion affinity experiments using UV-Vis spectrophotometry and multinuclei NMR spectroscopy. Compounds 1 and 3 exhibited selective binding to fluoride anion but did not interact with other halides (Cl- and Br-). Quantum chemical calculations were performed to understand the structure and nature of bonding interactions in these compounds, as well as to comprehend the specific bonding affinity to fluoride over other halide ions.

Correction: Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2.

Correction for 'Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2' by Aditya G. Rao et al., Phys. Chem. Chem. Phys., 2021, DOI: 10.1039/d0cp05314g.

Histidine protonation controls structural heterogeneity in the cyanobacteriochrome AnPixJg2.

Cyanobacteriochromes are compact and spectrally diverse photoreceptor proteins that bind a linear tetrapyrrole as a chromophore. They show photochromicity by having two stable states that can be interconverted by the photoisomerization of the chromophore. These photochemical properties make them an attractive target for biotechnological applications. However, their application is impeded by structural heterogeneity that reduces the yield of the photoconversion. The heterogeneity can originate either from the chromophore structure or the protein environment. Here, we study the origin of the heterogeneity in AnPixJg2, a representative member of the red/green cyanobacteriochrome family, that has a red absorbing parental state and a green absorbing photoproduct state. Using molecular dynamics simulations and umbrella sampling we have identified the protonation state of a conserved histidine residue as a trigger for structural heterogeneity. When the histidine is in a neutral form, the chromophore structure is homogenous, while in a positively charged form, the chromophore is heterogeneous with two different conformations. We have identified a correlation between the protonation of the histidine and the structural heterogeneity of the chromophore by detailed characterization of the interactions in the protein binding site. Our findings reconcile seemingly contradicting spectroscopic studies that attribute the heterogeneity to different sources. Furthermore, we predict that circular dichroism can be used as a diagnostic tool to distinguish different substates.

Dipole Moment Propels π-Stacking of Heterodimers of Fluorophenylacetylenes.

Electronic and vibrational spectroscopic investigations in combination with quantum chemical calculations were carried out to probe the formation of four sets of heterodimers of phenylacetylene with 2-fluorohenylacetylene, 3-fluorophenylacetylene, 4-fluorophenylacetylene, and 2,6-difluorophenylacetylene. The interaction of phenylacetylene with fluorophenylacetylenes leads to marginal (2-9 cm-1) red-shifts in the acetylenic C-H stretching frequencies of fluorophenylacetylenes, which suggests that constituent monomers are minimally perturbed in the heterodimer. On the other hand, the density-functional-theory-based calculations indicate that π-stacked structures outweigh other structures incorporating C-H···π and C-H···F interactions by about 8 kJ mol-1 or more. The IR spectra in the acetylenic C-H stretching region were interpreted based on the perturbed dipole model, which suggests formation of predominantly antiparallel π-stacked structures, propelled by dipole moment. However, the energy decomposition analysis suggests that among stabilizing components dispersion dominates, while electrostatics plays a pivotal role in the formation of the π-stacked structures. Interestingly, the ability of 2-fluorophenylacetylene and 2,6-difluorophenylacetylene to π-stack differs significantly, even though both of them have almost identical dipole moments and the dipole moment propels the formation of π-stack structures. These results suggest π-stacking transcends the classical electrostatic description in terms of dipole moment.

π-Stacking Driven Aggregation and Folding of Squaramides.

Competing noncovalent interactions play a pivotal role in the folding and assembly of three-dimensional structures, especially in flexible molecules. Calculations using density functional theory reveal that two squaramide rings aggregate to form a slipped antiparallel π-stacked dimer with high propensity. This π-π stacking interaction is used to design foldamers in which the squaramides are tethered by a simple methylene bridge, and consequently, the structure folds on to itself incorporating a "turn" element. The variation in relative energy with respect to change in dihedral angle for these foldamers show that for all the structures two rings are displaced in space and the folding potential is asymmetric, starting from seemingly symmetric molecules. The addition of successive squaramide rings connected with simple methylene bridges leads to the formation of higher-order structures with a "Turn-Stack-Turn" structural motif. The "Turn-Stack-Turn" motif can be used in designing new synthetic foldamers which could potentially mimic closely related biological systems. Further, it was found that the aggregation of the folded structures was energetically favored over the unfolded structures. The present set of calculations are important in light of the fact that these simple methylene bridged squaramide rings present synthetic challenges.

Modern quantum chemistry with [Open]Molcas.

MOLCAS/OpenMolcas is an ab initio electronic structure program providing a large set of computational methods from Hartree-Fock and density functional theory to various implementations of multiconfigurational theory. This article provides a comprehensive overview of the main features of the code, specifically reviewing the use of the code in previously reported chemical applications as well as more recent applications including the calculation of magnetic properties from optimized density matrix renormalization group wave functions.

Elusive Double-Eight-Ring Zeolitic Secondary Building Unit.

The double-eight-ring (D8R), an elusive secondary building unit of zeolites, has been stabilized for the first time, both in solution and solid-state. The present study further establishes that any of the three double-ring building blocks of zeolites, viz. D4R, D6R and D8R ([ArPO3Zn(L)]n (n = 4, 6 or 8)), can be preferentially isolated (over the other two) through a careful choice of metal source, aryl phosphate and ancillary ligand, apart from maintaining a meticulous control on the reaction conditions.

π-Stacked Dimers of Fluorophenylacetylenes: Role of Dipole Moment.

The homodimers of singly fluorine-substituted phenylacetylenes were investigated using electronic and vibrational spectroscopic methods in combination with density functional theory calculations. The IR spectra in the acetylenic C-H stretching region show a marginal red shift for the dimers relative to the monomers. Further, the marginal red shifts indicate that the acetylenic group in all the dimers is minimally perturbed relative to the corresponding monomer. The observed spectra were assigned to a set of π-stacked structures within an energy range of 1.5 kJ mol-1, which differ in the relative orientation of the two monomers on the basis of M06-2X/aug-cc-pVTZ level calculation. The observed red shift in the acetylenic C-H stretching vibration of the dimers suggests that the antiparallel structures contribute predominantly based on a simple coupled dipole model. Energy decomposition analysis using symmetry-adapted perturbation theory indicates that dispersion plays a pivotal role in π-π stacking with appreciable contribution of electrostatics. The stabilization energies of fluorophenylacetylene dimers follow the same ordering as their dipole moments, which suggests that dipole moment enhances the ability to form π-stacked structures.

Spectroscopic and Ab†Initio Investigation of C-H⋠⋠⋠N Hydrogen-Bonded Complexes of Fluorophenylacetylenes: Frequency Shifts and Correlations.

The C-H⋅⋅⋅N hydrogen-bonded complexes of several fluorophenyacetylenes with ammonia and methylamine were characterized by a redshift in the acetylenic C-H stretching vibration of the phenylacetylene moiety. These redshifts were linearly correlated with the stabilization energies calculated at the CCSD(T)/CBS//MP2-aug-cc-pVDZ level. Analysis of various components of the interaction energy indicated that the observed redshifts were weakly correlated with the electrostatic component. The weaker linear correlation between the frequency shifts and the electrostatic component between two data sets can perhaps be attributed to the marginal differences in the Stark tuning rate and zero-field shifts. The induction and exchange-repulsion components were linearly correlated. However, the dispersion component depends on the nature of the hydrogen-bond acceptor and shows a quantum jump when the hydrogen-bond acceptor is changed from ammonia to methylamine. The observed linear correlation between the redshifts in the C-H stretching frequencies and the total stabilization energies is due to mutual cancellation of deviations from linearity between various components.

Three-Fold C 3-Symmetric Off-On Fluorescent Chemo-Sensors for Fluoride.

Three novel C 3-symmetric tris-salicylaldimine Schiff base based "off-on" fluorescence sensors have been designed and synthesized. The synthetic approach involves a simple imine bond (C = N) formation between 1,3,5-tris(4'-aminophenyl)benzene (TAPB) and 3,5-substituted salicylaldehydes. The presence of salicylaldehyde units on periphery of the tris-salicylaldimine Schiff bases masks the fluorescence of TAPB core. Interestingly, binding of fluoride ions to the salicylaldehyde units turns the fluorescence "on" in visible region. Fluoride ion detection limits for the present sensors have been calculated to be in the range of 0.17-3.0 ppm, which depends on the nature of the salicylaldehyde units.

Internal electric fields in small water clusters [(H2O)n; n = 2-6].

The electric field experienced by a water molecule within a water cluster depends on its position relative to the rest of the water molecules. The stabilization energies and the red-shifts in the donor O-H stretching vibrations in the water clusters increase with the cluster size concomitant with the increase in the electric field experienced by the donor O-H of a particular water molecule due to the hydrogen bonding network. The red-shifts in O-H stretching frequencies show a spread of about ±100 cm(-1) against the corresponding electric fields. Deviations from linearity were marked in the region of 100-160 MV cm(-1), which can be attributed to the strain in the hydrogen bonding network, especially for structures with DDAA and DDA motifs. The linear Stark effect holds up to 200 MV cm(-1) of internal electric field for the average red-shifts in the O-H stretching frequencies, with a Stark tuning rate of 2.4 cm(-1) (MV cm(-1))(-1), suggesting the validity of the classical model in small water clusters.

Octanuclear zinc phosphates with hitherto unknown cluster architectures: ancillary ligand and solvent assisted structural transformations thereof.

Structural variations in zinc phosphate cluster chemistry have been achieved through a careful selection of phosphate ligand, ancillary ligand, and solvent medium. The use of 4-haloaryl phosphates (X-dippH2) as phosphate source in conjunction with 2-hydroxypyridine (hpy) ancillary ligand in acetonitrile solvent resulted in the isolation of the first examples of octameric zinc phosphates [Zn8(X-dipp)8(hpy)4(CH3CN)2(H2O)2]·4H2O (X = Cl 2, Br 3) and not the expected tetranuclear D4R cubane clusters. Use of 2,3-dihydroxypyridine (dhpy) as ancillary ligand, under otherwise similar reaction conditions with the same set of phosphate ligands and solvent, resulted in isolation of another type of octanuclear zinc phosphate clusters {[(Zn8(X-dipp)4(X-dippH)4(dhpyH)4(dhpyH2)2(H2O)2]·2solvent} (X = Cl, solvent = MeCN 4; Br, solvent = H2O 5), as the only isolated products. X-ray crystal diffraction studies reveal that 2 and 3 are octanuclear clusters that are essentially formed by edge fusion of two D4R zinc phosphates. Although 4 and 5 are also octanuclear clusters, they exhibit a completely different cluster architecture and have been presumably formed by the ability of 2,3-dihydroxypyridine to bridge zinc centers in addition to the X-dipp ligands. Dissolution of both types of octanuclear clusters in DMSO followed by crystallization yields D4R cubanes [Zn(X-dipp)(DMSO)]4 (X = Cl 6, Br 7), in which the ancillary ligands such as hpy, H2O, and CH3CN originally present on the zinc centers of 2-5 have been replaced by DMSO. DFT calculations carried out to understand the preference of Zn8 versus Zn4 clusters in different solvent media reveal that use of CH3CN as solvent favors the formation of fused cubanes of the type 2 and 3, whereas use of DMSO as the solvent medium promotes the formation of D4R structures of the type 6 and 7. The calculations also reveal that the vacant exocluster coordination sites on the zinc centers at the bridgehead positions prefer coordination by water to hpy or CH3CN. Interestingly, the initially inaccessible D4R cubanes [Zn(X-dipp)(hpy)]4·2MeCN (X = Cl 8, Br 9) could be isolated as the sole products from the corresponding DMSO-decorated cubanes 6 and 7 by combining them with hpy in CH3CN.

The propargylbenzene dimer: C-H···π assisted π-π stacking.

The propargylbenzene dimer was investigated using mass selected electronic and infrared spectroscopy in combination with quantum chemical calculations. The IR spectrum in the acetylenic C-H stretching region indicates that the two propargylbenzene units in the dimer are in an almost identical environment. The stabilization energies calculated at various levels of theory predict that the anti-parallel structure is the most stable isomer. The observed spectra are assigned to π-stacked structures which incorporate C-H···π interaction. The symmetry-adapted perturbation theory (SAPT) based energy decomposition analysis reveals that electrostatics contributes around 35% while the rest is due to dispersion. Comparison with the phenylacetylene and toluene dimers indicates that the higher stabilization energy of the PrBz dimer can be attributed to the synergy between the π-π stacking and C-H···π interactions.

Spectroscopic and ab initio investigation of 2,6-difluorophenylacetylene-amine complexes: coexistence of C-H···N and lone-pair···π complexes and intermolecular coulombic decay.

Binary complexes of 2,6-difluorophenylacetylene with methylamine, dimethylamine, trimethylamine and triethylamine were investigated using one colour resonant two photon ionization and infrared-optical double resonance spectroscopic techniques combined with high level ab initio calculations. All four amines form CAc-H···N hydrogen-bonded complexes. Additionally trimethylamine and triethylamine form complexes characterized by Lp···π interactions, due to the electron deficient nature of the phenyl ring of 2,6-difluorophenylacetylene. The Lp···π interacting structure of the 2,6-difluorophenylacetylene-trimethylamine complex is about 1.5 kJ mol(-1) higher in energy than the CAc-H···N hydrogen-bonded structure, which is the global minimum. Energy decomposition analysis indicates that the electrostatics and dispersion interactions favour the formation of CAc-H···N and Lp···π complexes, respectively. Interestingly the CAc-H···N hydrogen-bonded complex of 2,6-difluorophenylacetylene-triethylamine showed a smaller shift in the acetylenic C-H stretching frequency than the 2,6-difluorophenylacetylene-trimethylamine complex. The observed fragmentation of the binary complexes of 2,6-difluorophenylacetylene with the four amines following resonant two-photon ionization can be explained on the basis of the intermolecular coulombic decay process.

Electrostatics determine vibrational frequency shifts in hydrogen bonded complexes.

The red-shifts in the acetylenic C-H stretching vibration of C-H∙∙∙X (X = O, N) hydrogen-bonded complexes increase with an increase in the basicity of the Lewis base. Analysis of various components of stabilization energy suggests that the observed red-shifts are correlated with the electrostatic component of the stabilization energy, while the dispersion modulates the stabilization energy.

Selective fluorescence sensing of polynitroaromatic explosives using triaminophenylbenzene scaffolds.

A supramolecular fluorophore, 1,3,5-tris(4'-aminophenyl)benzene (TAPB), selectively senses polynitroaromatic compounds (PNAC), viz. 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), picric acid (PA), m-dinitrobenzene (m-DNB) and p-dinitrobenzene (p-DNB) through donor-acceptor complexation. Steady-state and time resolved fluorescence measurements indicate predominantly static quenching of the TAPB fluorophore with TNT, DNT, m-DNB and p-DNB. In the case of PA, a new emissive band with a marginally longer lifetime emerges due to complex formation with TAPB. The selectivity of sensing action is rationalized through computation of HOMO and LUMO energies for both the fluorophore and the analytes using the M06-2X/6-311+G(d,p) level of theory. Practical utility of the fluorophore has also been demonstrated with TNT and DNT vapour.

Dynamics and mechanism of a light-driven chloride pump.

Chloride transport by microbial rhodopsins is an essential process for which molecular details such as the mechanisms that convert light energy to drive ion pumping and ensure the unidirectionality of the transport have remained elusive. We combined time-resolved serial crystallography with time-resolved spectroscopy and multiscale simulations to elucidate the molecular mechanism of a chloride-pumping rhodopsin and the structural dynamics throughout the transport cycle. We traced transient anion-binding sites, obtained evidence for how light energy is used in the pumping mechanism, and identified steric and electrostatic molecular gates ensuring unidirectional transport. An interaction with the π-electron system of the retinal supports transient chloride ion binding across a major bottleneck in the transport pathway. These results allow us to propose key mechanistic features enabling finely controlled chloride transport across the cell membrane in this light-powered chloride ion pump.

Π-Stacking in Heterodimers of Propargylbenzene with (Fluoro)phenylacetylenes.

The heterodimers of propargylbenzene (PrBz) with phenylacetylene (PHA) and monosubstituted fluorophenylacetylenes (FPHAs) were investigated using electronic and vibrational spectroscopic methods. The vibrational spectra in the acetylenic C-H stretching region show a marginal shift (0-4 cm-1) upon dimer formation, which suggests minimal perturbation of the acetylenic group. The M06-2X/aug-cc-pVDZ calculations indicate that the π-stacked structures are the most stable, followed by other structures. In general, structures incorporating aromatic C-H···π interactions are much higher in energy. The appearance of the spectra and the energy considerations clearly indicate the preference for the π-stacked structures. Furthermore, the observed trend in the stabilization energies for heterodimers with the three FPHAs is inversely proportional to the dipole moments of FPHAs. On the other hand, the absence of any clear trends in the electrostatic component of the interaction energy is attributed to the presence of the methylene group in PrBz.

Frontiers in Multiscale Modeling of Photoreceptor Proteins.

This perspective article highlights the challenges in the theoretical description of photoreceptor proteins using multiscale modeling, as discussed at the CECAM workshop in Tel Aviv, Israel. The participants have identified grand challenges and discussed the development of new tools to address them. Recent progress in understanding representative proteins such as green fluorescent protein, photoactive yellow protein, phytochrome, and rhodopsin is presented, along with methodological developments.