Nanna Holmgaard List

Molecular-Level Insight into the Spectral Tuning Mechanism of the DsRed Chromophore.

We present a detailed study of the protein environmental effects on the one- and two-photon absorption (1PA and 2PA, respectively) properties of the S0-S1 transition in the DsRed protein using the polarizable embedding density functional theory formalism. We find that steric factors and chromophore-protein interactions act in concert to enhance the 2PA activity inside the protein while adversely blue-shifting the 1PA maximum. A two-state model reveals that the 2PA intensity gain is primarily governed by the increased change in the permanent dipole moment between the ground and the excited states acquired inside the protein. Our results indicate that this mainly is attributable to counter-directional contributions stemming from Lys163 and the conserved Arg95 with the former additionally identified as a key residue in the color tuning mechanism. The results provide new insight into the tuning mechanism of DsRed and suggest a possible strategy for simultaneous improvement of its 1PA and 2PA properties.

The Multi-Configuration Self-Consistent Field Method Within a Polarizable Embedded Framework

We present a detailed derivation of Multi-Configuration Self-Consistent Field (MCSCF) optimization and linear response equations within the polarizable embedding scheme: PE-MCSCF. The MCSCF model enables a proper description of multiconfigurational effects in reaction paths, spin systems, excited states, and other properties which cannot be described adequately with current implementations of polarizable embedding in density functional or coupled cluster theories. In the PE-MCSCF scheme the environment surrounding the central quantum mechanical system is represented by distributed multipole moments and anisotropic dipole-dipole polarizabilities. The PE-MCSCF model has been implemented in DALTON. As a preliminary application, the low lying valence states of acetone and uracil in water has been calculated using Complete Active Space Self-Consistent Field (CASSCF) wave functions. The dynamics of the water environment have been simulated using a series of snapshots generated from classical Molecular Dynamics. The calculated shifts from gas-phase to water display between good and excellent correlation with experiment and previous calculations. As an illustration of another area of potential applications we present calculations of electronic transitions in the transition metal complex, [Fe(NO)(CN)5](2-) in a micro-solvated environment. This system is highly multiconfigurational and the influence of solvation is significant.

Toward Reliable Prediction of the Energy Ladder in Multichromophoric Systems: A Benchmark Study on the FMO Light-Harvesting Complex.

We present an evaluation of the performance of various single-reference QM methods for the prediction of the relative site energies and transition moments of the Q bands in the bacteriochlorophyll a (BChl a) pigments of the Fenna-Matthew-Olson (FMO) complex. We examine the relative merits of ZINDO, CIS, TD-DFT (with the functionals PBE, BLYP, PBE0, B3LYP, and CAM-B3LYP) and RI-CC2 in reproducing the variations across the pigments that occur as a consequence of geometrical and electrostatic effects of the FMO complex by comparison to DFT-BHLYP/MRCI. We find that these pigments are near-multiconfigurational in nature and, thus, constitute critical cases for the RI-CC2 method. The commonly used ZINDO method is fairly reliable for the site energies of the isolated pigments; however, it overestimates the coupling to the environment, thereby leading to variations across the embedded pigments that are too drastic. The overall best performance is provided by the investigated TD-DFT methods, where PBE0 is found to be slightly superior to the other functionals tested.

Accuracy of Protein Embedding Potentials: An Analysis in Terms of Electrostatic Potentials.

Quantum-mechanical embedding methods have in recent years gained significant interest and may now be applied to predict a wide range of molecular properties calculated at different levels of theory. To reach a high level of accuracy in embedding methods, both the electronic structure model of the active region and the embedding potential need to be of sufficiently high quality. In fact, failures in quantum mechanics/molecular mechanics (QM/MM)-based embedding methods have often been associated with the QM/MM methodology itself; however, in many cases the reason for such failures is due to the use of an inaccurate embedding potential. In this paper, we investigate in detail the quality of the electronic component of embedding potentials designed for calculations on protein biostructures. We show that very accurate explicitly polarizable embedding potentials may be efficiently designed using fragmentation strategies combined with single-fragment ab initio calculations. In fact, due to the self-interaction error in Kohn-Sham density functional theory (KS-DFT), use of large full-structure quantum-mechanical calculations based on conventional (hybrid) functionals leads to less accurate embedding potentials than fragment-based approaches. We also find that standard protein force fields yield poor embedding potentials, and it is therefore not advisable to use such force fields in general QM/MM-type calculations of molecular properties other than energies and structures.

Dehydroergosterol as an analogue for cholesterol : why it mimics cholesterol so well—or does It?

Although dehydroergosterol (DHE) is one of the most commonly used cholesterol (CHOL) reporters, it has remained unclear why it performs well compared with most other CHOL analogues and what its possible limitations are. We present a comprehensive study of the properties of DHE using a combination of time-resolved fluorescence spectroscopy, quantum-mechanical electronic structure computations, and classical atomistic molecular dynamics simulations. We first establish that DHE mimics CHOL behavior, as previous studies have suggested, and then move on to elucidate and discuss the particular properties that render DHE so superior. We found that the main reason why DHE mimics CHOL so well is due to its ability to stand upright in a membrane in a manner that is almost identical to that of CHOL. The minor difference in how DHE and CHOL tilt with respect to membrane normal has only faint effects on structural membrane properties, and even the lateral pressure profiles of model membranes with CHOL or DHE are almost identical. These results suggest that the mechanical/elastic effects of DHE on the function of mechanically sensitive membrane proteins are not substantially different from those of CHOL. Our study highlights similar dynamical behavior of CHOL and DHE, which implies that DHE can mimic CHOL in processes with free energies close to the thermal energy.

A click chemistry approach to pleuromutilin derivatives, part 2: conjugates with acyclic nucleosides and their ribosomal binding and antibacterial activity.

Pleuromutilin is an antibiotic that binds to bacterial ribosomes and thereby inhibit protein synthesis. A new series of semisynthetic pleuromutilin derivatives were synthesized by a click chemistry strategy. Pleuromutilin was conjugated by different linkers to a nucleobase, nucleoside, or phenyl group, as a side-chain extension at the C22 position of pleuromutilin. The linkers were designed on the basis of the best linker from our first series of pleuromutilin derivatives following either conformational restriction or an isosteric methylene to oxygen exchange. The binding of the new compounds to the Escherichia coli ribosome was investigated by molecular modeling and chemical footprinting of nucleotide U2506, and it was found that all the derivatives bind to the specific site and most of them better than pleuromutilin itself. The effect of the side-chain extension was also explored by chemical footprinting of nucleotide U2585, and the results showed that all the compounds interact with this position to varying degrees. Derivatives with a conformational restriction of the linker generally had a higher affinity than derivatives with an isosteric exchange of one of the carbons in the linker with a hydrophilic oxygen. A growth inhibition assay with three different bacterial strains showed significant activity of several of the new compounds.

Relation between Nonlinear Optical Properties of Push-Pull Molecules and Metric of Charge Transfer Excitations.

We establish the relationships between the metric of charge transfer excitation (Δr) for the bright ππ* state and the two-photon absorption probability as well as the first hyperpolarizability for two families of push-pull π-conjugated systems. As previously demonstrated by Guido et al. (J. Chem. Theory Comput. 2013, 9, 3118-3126), Δr is a measure for the average hole-electron distance upon excitation and can be used to discriminate between short- and long-range electronic excitations. We indicate two new benefits from using this metric for the analyses of nonlinear optical properties of push-pull systems. First, the two-photon absorption probability and the first hyperpolarizability are found to be interrelated through Δr; if β ∼ (Δr)(k), then roughly, δ(TPA) ∼ (Δr)(k+1). Second, a simple power relation between Δr and the molecular hyperpolarizabilities of push-pull systems offers the possibility of estimating properties for longer molecular chains without performing calculations of high-order response functions explicitly. We further demonstrate how to link the hyperpolarizabilities with the chain length of the push-pull π-conjugated systems through the metric of charge transfer.

Averaged Solvent Embedding Potential Parameters for Multiscale Modeling of Molecular Properties

We derive and validate averaged solvent parameters for embedding potentials to be used in polarizable embedding quantum mechanics/molecular mechanics (QM/MM) molecular property calculations of solutes in organic solvents. The parameters are solvent-specific atom-centered partial charges and isotropic polarizabilities averaged over a large number of geometries of solvent molecules. The use of averaged parameters reduces the computational cost to obtain the embedding potential, which can otherwise be a rate-limiting step in calculations involving large environments. The parameters are evaluated by analyzing the quality of the resulting molecular electrostatic potentials with respect to full QM potentials. We show that a combination of geometry-specific parameters for solvent molecules close to the QM region and averaged parameters for solvent molecules further away allows for efficient polarizable embedding multiscale modeling without compromising the accuracy. The results are promising for the development of general embedding parameters for biomolecules, where the reduction in computational cost can be considerable.

Beyond the electric-dipole approximation : A formulation and implementation of molecular response theory for the description of absorption of electromagnetic field radiation

We present a formulation of molecular response theory for the description of a quantum mechanical molecular system in the presence of a weak, monochromatic, linearly polarized electromagnetic field without introducing truncated multipolar expansions. The presentation focuses on a description of linear absorption by adopting the energy-loss approach in combination with the complex polarization propagator formulation of response theory. Going beyond the electric-dipole approximation is essential whenever studying electric-dipole-forbidden transitions, and in general, non-dipolar effects become increasingly important when addressing spectroscopies involving higher-energy photons. These two aspects are examined by our study of the near K-edge X-ray absorption fine structure of the alkaline earth metals (Mg, Ca, Sr, Ba, and Ra) as well as the trans-polyenes. In following the series of alkaline earth metals, the sizes of non-dipolar effects are probed with respect to increasing photon energies and a detailed assessment of results is made in terms of studying the pertinent transition electron densities and in particular their spatial extension in comparison with the photon wavelength. Along the series of trans-polyenes, the sizes of non-dipolar effects are probed for X-ray spectroscopies on organic molecules with respect to the spatial extension of the chromophore.

Lanczos-driven coupled–cluster damped linear response theory for molecules in polarizable environments

We present an extension of a previously reported implementation of a Lanczos-driven coupled-cluster (CC) damped linear response approach to molecules in condensed phases, where the effects of a surrounding environment are incorporated by means of the polarizable embedding formalism. We are specifically motivated by a twofold aim: (i) computation of core excitations in realistic surroundings and (ii) examination of the effect of the differential response of the environment upon excitation solely related to the CC multipliers (herein denoted the J matrix) in computations of excitation energies and transition moments of polarizable-embedded molecules. Numerical calculations demonstrate that the differential polarization of the environment due to the first-order CC multipliers provides only minor contributions to the solvatochromic shift for all transitions considered. We thus complement previous works by confirming numerically the validity of the routinely invoked neglect of the J matrix contribution as well as motivating future use of the approximation that offers a reduction of the dimensionality of the eigenvalue problem. Preliminary applications to K-edge absorption of liquid water and aqueous acrolein are presented and highlight the importance of the environment that gives rise to transition-specific shifts.