Vibrational Circular Dichroism Spectroscopy with a Classical Polarizable Force Field: Alanine in the Gas and Condensed Phases.

Polarizable force fields are an essential component for the chemically accurate modeling of complex molecular systems with a significant degree of fluxionality, beyond harmonic or perturbative approximations. In this contribution we examine the performance of such an approach for the vibrational spectroscopy of the alanine amino acid, in the gas and condensed phases, from the Fourier transform of appropriate time correlation functions generated along molecular dynamics (MD) trajectories. While the infrared (IR) spectrum only requires the electric dipole moment, the vibrational circular dichroism (VCD) spectrum further requires knowledge of the magnetic dipole moment, for which we provide relevant expressions to be used with polarizable force fields. The AMOEBA force field was employed here to model alanine in the neutral and zwitterionic isolated forms, solvated by water or nitrogen, and as a crystal. Within this framework, comparison of the electric and magnetic dipole moments to those obtained with nuclear velocity perturbation theory based on density-functional theory for the same MD trajectories are found to agree well with one another. The statistical convergence of the IR and VCD spectra is examined and found to be more demanding in the latter case. Comparisons with experimental frequencies are also provided for the condensed phases.

Vibrational Circular Dichroism Spectroscopy of Chiral Molecular Crystals: Insights from Theory.

Chirality is a curious phenomenon that appears in various forms. While the concept of molecular (RS-)chirality is ubiquitous in chemistry, there are also more intricate forms of structural chirality. One of them is the enantiomorphism of crystals, especially molecular crystals, that describes the lack of mirror symmetry in the unit cell. Its relation to molecular chirality is not obvious, but still an open question, which can be addressed with chiroptical tools. Vibrational circular dichroism (VCD) denotes chiral infrared (IR) spectroscopy that is susceptible to both, the molecular as well as the intermolecular space by means of vibrational transitions. When carried out in the solid state, VCD delivers a very rich set of non-local contributions that are determined by crystal packing and collective motion. Since its discovery in the 1970s, VCD has become the method of choice for the determination of absolute configurations, but its applicability reaches beyond towards the study of different crystal forms and polymorphism. This brief review summarises the theoretical concepts of crystal chirality and how computations of solid-state VCD can shed light into the intimate connection of chiral structure and vibrational optical activity.

Influence of the environment on the infrared spectrum of alanine: An effective mode analysis.

The vibrational spectrum of the alanine amino acid was computationally determined in the infrared range 1000-2000 cm-1, under various environments encompassing the gas, hydrated, and crystalline phases, by means of classical molecular dynamics trajectories, carried out with the Atomic Multipole Optimized Energetics for Biomolecular Simulation polarizable force field. An effective mode analysis was performed, in which the spectra are optimally decomposed into different absorption bands arising from well-defined internal modes. In the gas phase, this analysis allows us to unravel the significant differences between the spectra obtained for the neutral and zwitterionic forms of alanine. In condensed phases, the method provides invaluable insight into the molecular origins of the vibrational bands and further shows that peaks with similar positions can be traced to rather different molecular motions.

How Crystal Symmetry Dictates Non-Local Vibrational Circular Dichroism in the Solid State.

Solid-State Vibrational Circular Dichroism (VCD) can be used to determine the absolute structure of chiral crystals, but its interpretation remains a challenge in modern spectroscopy. In this work, we investigate the effect of a twofold screw axis on the solid-state VCD spectrum in a combined experimental and theoretical analysis of P21 crystals of (S)-(+)-1-indanol. Even though the space group is achiral, a single proper symmetry operation has an important impact on the VCD spectrum, which reflects the supramolecular chirality of the crystal. Distinguishing between contributions originating from molecular chirality and from chiral crystal packing, we find that while IR absorption hardly depends on the symmetry of the space group, the situation is different for VCD, where completely new non-local patterns emerge. Understanding the two underlying mechanisms, namely gauge transport and direct coupling, will help to use VCD to distinguish polymorphic forms.

The important role of non-covalent interactions for the vibrational circular dichroism of lactic acid in aqueous solution.

We present a computational study of vibrational circular dichroism (VCD) in solutions of (S)-lactic acid, relying on ab initio molecular dynamics (AIMD) and full solvation with bulk water. We discuss the effect of the hydrogen bond network on the aggregation behaviour of the acid: while aggregates of the solute represent conditions encountered in a weakly interacting solvent, the presence of water drastically interferes with the clusters - more strongly than originally anticipated. For both scenarios we computed the VCD spectra by means of nuclear velocity perturbation theory (NVPT). The comparison with experimental data allows us to establish a VCD-structure relationship that includes the solvent network around the chiral solute. We suggest that fundamental modes with strong polarisation such as the carbonyl stretching vibration can borrow VCD from the chirally restructured solvent cage, which extends the common explanatory models of VCD generation in aqueous solution.

Computation of Solid-State Vibrational Circular Dichroism in the Periodic Gauge.

We introduce a new theoretical formalism to compute solid-state vibrational circular dichroism (VCD) spectra from molecular dynamics simulations. Having solved the origin-dependence problem of the periodic magnetic gauge, we present IR and VCD spectra of (1S,2S)-trans-1,2-cyclohexanediol obtained from first-principles molecular dynamics calculations and nuclear velocity perturbation theory, along with the experimental results. Because the structure model imposes periodic boundary conditions, the common origin of the rotational strength has hitherto been ill-defined and was approximated by means of averaging multiple origins. The new formalism reconnects the periodic model with the finite physical system and restores gauge freedom. It nevertheless fully accounts for nonlocal spatial couplings from the gauge transport term. We show that even for small simulation cells the rich nature of solid-state VCD spectra found in experiments can be reproduced to a very satisfactory level.

Hydrogen Bond between a Tyrosine Residue and the C-Ring Propionate Has a Direct Influence on Conformation and Absorption of the Bilin Cofactor in Red/Green Cyanobacteriochromes.

Cyanobacteriochromes (CBCRs) are photoreceptors of the phytochrome superfamily showing remarkable variability in the wavelengths of the first electronic transition-sometimes denoted as Q band-compared to canonical phytochromes. Both classes carry the same cofactor, a bilin, but the molecular basis for the wide variation of their absorption properties is still a matter of debate. The interaction between the cofactor and the surrounding protein moiety has been proposed as a possible tuning factor. Here, we address the impact of hydrogen-bonding interaction between the covalently bound tetrapyrrole cofactor (phycocyanobilin, PCB) and a conserved tyrosine residue (Y302) in the second GAF (cGMP-specific phosphodiesterase, adenylyl cyclases, and FhlA) domain of the red-/green-switching CBCR AnPixJ (AnPixJg2). In the wild type, AnPixJg2 shows absorption maxima of 648 and 543 nm for the dark-adapted (Pr) and photoproduct (Pg) states, respectively. The Y302F mutation leads to the occurrence of an additional absorption band at 687 nm, which is assigned to a new spectroscopically identified sub-state called PIII. Similar spectral changes result upon mutating the Y302F-homologue in another representative red-/green-switching CBCR, Slr1393g3. Molecular dynamics simulations on the dark-adapted state suggest that the removal of the hydrogen bond leads to an additional PCB sub-state differing in its A- and D-ring geometries. The origin of the Q band satellite in the dark-adapted state is discussed.

Carbon Atoms Speaking Out: How the Geometric Sensitivity of 13C Chemical Shifts Leads to Understanding the Colour Tuning of Phycocyanobilin in Cph1 and AnPixJ.

We present a combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics-statistical approach for the interpretation of nuclear magnetic resonance (NMR) chemical shift patterns in phycocyanobilin (PCB). These were originally associated with colour tuning upon photoproduct formation in red/green-absorbing cyanobacteriochrome AnPixJg2 and red/far-red-absorbing phytochrome Cph1Δ2. We pursue an indirect approach without computation of the absorption frequencies since the molecular geometry of cofactor and protein are not accurately known. Instead, we resort to a heuristic determination of the conjugation length in PCB through the experimental NMR chemical shift patterns, supported by quantum chemical calculations. We have found a characteristic correlation pattern of 13C chemical shifts to specific bond orders within the π-conjugated system, which rests on the relative position of carbon atoms with respect to electron-withdrawing groups and the polarisation of covalent bonds. We propose the inversion of this regioselective relationship using multivariate statistics and to apply it to the known experimental NMR chemical shifts in order to predict changes in the bond alternation pattern. Therefrom the extent of electronic conjugation, and eventually the change in absorption frequency, can be derived. In the process, the consultation of explicit mesomeric formulae plays an important role to qualitatively account for possible conjugation scenarios of the chromophore. While we are able to consistently associate the NMR chemical shifts with hypsochromic and bathochromic shifts in the Pg and Pfr, our approach represents an alternative method to increase the explanatory power of NMR spectroscopic data in proteins.

Assessing cluster models of solvation for the description of vibrational circular dichroism spectra: synergy between static and dynamic approaches.

Solvation effects are essential for defining the shape of vibrational circular dichroism (VCD) spectra. Several approaches have been proposed to include them into computational models for calculating VCD signals, in particular those resting on the "cluster-in-a-liquid" model. Here we examine the capabilities of this ansatz on the example of flexible (1S,2S)-trans-1-amino-2-indanol solvated in dimethyl sulfoxide (DMSO). We compare cluster sets obtained from static calculations with results from explicit molecular dynamics (MD) trajectories based on either force field (FF) or first-principles (FP) methods. While the FFMD approach provides a broader sampling of configurational space, FPMD and time-correlation functions of dipole moments account for anharmonicity and entropy effects in the VCD calculation. They provide a means to evaluate the immediate effect of the solvent on the spectrum. This survey singles out several challenges associated with the use of clusters to describe solvation effects in systems showing shallow potential energy surfaces and non-covalent interactions. Static structures of clusters involving a limited number of solvent molecules satisfactorily capture the main effects of solvation in the bulk limit on the VCD spectra, if these structures are correctly weighted. The importance of taking into consideration their fluxionality, i.e. different solvent conformations sharing a same hydrogen bond pattern, and the limitations of small clusters for describing the solvent dynamics are discussed.

Chiral Crystal Packing Induces Enhancement of Vibrational Circular Dichroism.

We demonstrate that molecular vibrations with originally low or zero intensity in a vibrational circular dichroism (VCD) spectrum attain chirality in molecular crystals by coordinated motion of the atoms. Ab initio molecular dynamics simulations of anharmonic solid-state VCD spectra of l-alanine crystals reveal how coherent vibrational modes exploit the space group's chirality, leading to non-local, enhanced VCD features, most significantly in the carbonyl region of the spectrum. The VCD-enhanced signal is ascribed to a helical arrangement of the oscillators in the crystal layers. No structural irregularities need to be considered to explain the amplification, but a crucial point lies in the polarization of charge, which requires an accurate description of the electronic structure. Delivering a quantitative atomic conception of supramolecular chirality induction, our ab initio scheme is applicable well beyond molecular crystals, for example, to address VCD in proteins and related compounds.

Structural heterogeneity in a parent ground-state structure of AnPixJg2 revealed by theory and spectroscopy.

We investigated the red absorbing, dark stable state (Pr state) of the second GAF domain of the cyanobacteriochrome AnPixJ (AnPixJg2) by a molecular dynamics simulation of 1 µs duration. Our results reveal two distinct conformational isoforms of the chromophore, from which only one was known from crystallographic experiments. The interconversion between both isoforms is accompanied by alterations in the hydrogen bond pattern between the chromophore and the protein and the solvation structure of the chromophore binding pocket. The existence of sub-states in the Pr form of AnPixJg2 is supported by the results from experimental 13C MAS NMR spectroscopy. Our finding is consistent with the observation of structural heterogeneity in other cyanobacteriochromes and phytochromes.

Quantum cluster equilibrium model of N-methylformamide-water binary mixtures.

The established quantum cluster equilibrium (QCE) approach is refined and applied to N-methylformamide (NMF) and its aqueous solution. The QCE method is split into two iterative cycles: one which converges to the liquid phase solution of the QCE equations and another which yields the gas phase. By comparing Gibbs energies, the thermodynamically stable phase at a given temperature and pressure is then chosen. The new methodology avoids metastable solutions and allows a different treatment of the mean-field interactions within the gas and liquid phases. These changes are of crucial importance for the treatment of binary mixtures. For the first time in a QCE study, the cis-trans-isomerism of a species (NMF) is explicitly considered. Cluster geometries and frequencies are calculated using density functional theory (DFT) and complementary coupled cluster single point energies are used to benchmark the DFT results. Independent of the selected quantum-chemical method, a large set of clusters is required for an accurate thermodynamic description of the binary mixture. The liquid phase of neat NMF is found to be dominated by the cyclic trans-NMF pentamer, which can be interpreted as a linear trimer that is stabilized by explicit solvation of two further NMF molecules. This cluster reflects the known hydrogen bond network preferences of neat NMF.

Heterobimetallic complexes with highly flexible 1,1'-bis(phospholanoalkyl)ferrocene ligands.

The two highly flexible ligands 1,1'-bis(4-phospholanobutyl)ferrocene (5a) and 1,1'-bis(5-phospholanopentyl)ferrocene (5b) reacted with [PtCl2(cod)] (cod = 1,5-cyclooctadiene), [AuCl(tht)] (tht = tetrahydrothiophene) and [{RhCl(CO)2}2] to give the respective chelate complexes cis-[PtCl2(5a,b-κ(2)P,P')] (7a,b), [AuCl(5a,b-κ(2)P,P')] (8a,b) and trans-[RhCl(CO)(5b-κ(2)P,P')] (9b). Treatment of 5a,b with selenium gave the corresponding selenides 6a,b. All compounds have been fully characterised by NMR ((1)H, (13)C, (31)P) and IR spectroscopy and mass spectrometry. In addition, crystal structures of 6a, 7b, 8a,b and 9b were determined by X-ray crystallography. Furthermore, the rhodium-catalysed hydroformylation of 1-octene has been studied with ligand 5b.