Automated Quantum Chemistry-Based Calculation of Optical Rotation for Large Flexible Molecules.

The calculation of optical rotation (OR, [α]D) for nonrigid molecules was limited to small systems due to the challenging problem of generating reliable conformer ensembles, calculating accurate Boltzmann populations and the extreme sensitivity of the OR to the molecules' three-dimensional structure. Herein, we describe and release the crenso workflow for the automated computation of conformer ensembles in solution and corresponding [α]D values for flexible molecules. A comprehensive set of 28 organic drug molecules (28-144 atoms) with experimentally determined values is used in our assessment. In all cases, the correct OR sign is obtained with an overall mean relative deviation of 72% (mean absolute deviation of 82 °[dm(g/cm3)]-1 for experimental values in the range -160 to 287 °[dm(g/cm3)]-1). We show that routine [α]D computations for very flexible, biologically active molecules are both feasible and reproducible in about a day of computation time on a standard workstation computer. Furthermore, we observed that the effect of energetically higher-lying structures in the ensemble on the OR is often averaged out and that in 23 out of 28 cases, the correct OR sign is obtained by just considering only the lowest free energy conformer. In four example cases, we show that the approach can also describe the OR of pairs of flexible diastereomers properly. In summary, even very sensitive, multifactorial physicochemical properties appear reliably predictable with minimal user input from efficiently automated quantum chemical methods.

Sensory Perception of Non-Deuterated and Deuterated Organic Compounds.

The chemical background of olfactory perception has been subject of intensive research, but no available model can fully explain the sense of smell. There are also inconsistent results on the role of the isotopology of molecules. In experiments with human subjects it was found that the isotope effect is weak with acetone and D6 -acetone. In contrast, clear differences were observed in the perception of octanoic acid and D15 -octanoic acid. Furthermore, a trained sniffer dog was initially able to distinguish between these isotopologues of octanoic acid. In chromatographic measurements, the respective deuterated molecule showed weaker interaction with a non-polar liquid phase. Quantum chemical calculations give evidence that deuterated octanoic acid binds more strongly to a model receptor than non-deuterated. In contrast, the binding of the non-deuterated molecule is stronger with acetone. The isotope effect is calculated in the framework of statistical mechanics. It results from a complicated interplay between various thermostatistical contributions to the non-covalent free binding energies and it turns out to be very molecule-specific. The vibrational terms including non-classical zero-point energies play about the same role as rotational/translational contributions and are larger than bond length effects for the differential isotope perception of odor for which general rules cannot be derived.

Simplified time-dependent density functional theory (sTD-DFT) for molecular optical rotation.

Theoretical methods able to screen large sets (e.g., conformers) of possibly large compounds are needed in many typical quantum chemistry applications. For this purpose, we here extend the well-established simplified time-dependent density functional theory (sTD-DFT) method for the calculation of optical rotation. This new scheme is benchmarked against 42 compounds of the OR45 set as well as thirteen helicene derivatives and one bio-molecular system. The sTD-DFT method yields optical rotations in good quantitative agreement with experiment for compounds with a valence-dominated response, e.g., conjugated π-systems, at a small fraction of the computational cost compared to TD-DFT (1-3 orders of magnitude speed-up). For smaller molecules with a Rydberg state dominated response, the agreement between TD-DFT and the simplified version using standard hybrid functionals is somewhat worse but still reasonable for typical applications. Our new implementation in the stda code enables computations for systems with up to 1000 atoms, e.g., for studying flexible bio-molecules.

Quantum Chemical Calculation of Molecular and Periodic Peptide and Protein Structures.

Special-purpose classical force fields (FFs) provide good accuracy at very low computational cost, but their application is limited to systems for which potential energy functions are available. This excludes most metal-containing proteins or those containing cofactors. In contrast, the GFN2-xTB semiempirical quantum chemical method is parametrized for almost the entire periodic table. The accuracy of GFN2-xTB is assessed for protein structures with respect to experimental X-ray data. Furthermore, the results are compared with those of two special-purpose FFs, HF-3c, PM6-D3H4X, and PM7. The test sets include proteins without any prosthetic groups as well as metalloproteins. Crystal packing effects are examined for a set of smaller proteins to validate the molecular approach. For the proteins without prosthetic groups, the special purpose FF OPLS-2005 yields the smallest overall RMSD to the X-ray data but GFN2-xTB provides similarly good structures with even better bond-length distributions. For the metalloproteins with up to 5000 atoms, a good overall structural agreement is obtained with GFN2-xTB. The full geometry optimizations of protein structures with on average 1000 atoms in wall-times below 1 day establishes the GFN2-xTB method as a versatile tool for the computational treatment of various biomolecules with a good accuracy/computational cost ratio.

Dynamic Structural Effects on the Second-Harmonic Generation of Tryptophane-Rich Peptides and Gramicidin A.

Peptide chains can model endogenous biotags for applications in second-harmonic imaging microscopy. Such structures are flexible which may strongly affect their structure-property relationship. Here, we explore quantum-mechanically the conformational space of a set of tryptophan-rich model peptides. This has become feasible because of the recently proposed meta-dynamics method based on efficient tight-binding (TB) calculations. The TB version of the simplified time-dependent density functional theory (sTD-DFT-xTB) method is used to evaluate the first hyperpolarizability (ß). These new tools enable us to calculate nonlinear optical properties for systems with several thousand atoms and/or to screen large structure ensembles. First, we show that the indole chromophore in tryptophan residues dominates the ß response of these systems. Their relative orientation mostly determines the global ß tensor and affects the static ß response. The results underline the importance of finding low-energy conformers for modeling ß of flexible molecules. Additionally, we compare calculated and extrapolated experimental static ß. The sTD-DFT-xTB method is capable of providing reliable second-harmonic generation values for tryptophan-rich systems at a fraction of the computational cost of the commonly used TD-DFT/TD-HF levels of theory.

Are Fully Conjugated Expanded Indenofluorenes Analogues and Diindeno[n]thiophene Derivatives Diradicals? A Simplified (Spin-Flip) Time-Dependent Density Functional Theory [(SF-)sTD-DFT] Study.

Polycyclic hydrocarbons are often used to understand the electronic structure of nanographene systems. Among them, indeno[1,2b]fluorene and indeno[1,2c]fluorene isomers present a central p-quinodimethane unit leading to unique optical properties. In this work, we characterized the absorption spectra of indeno[1,2b]fluorene and [2,1-c]diindeno[n]thiophene derivatives with (spin-flip) simplified time-dependent density functional theory [(SF-)sTD-DFT] methods. Note that the SF-sTD-DFT level of theory allows a computationally efficient treatment for large diradicals. To interpret spectra, we implemented natural transition orbitals (NTOs) at both SF-sTD-DFT and sTD-DFT levels. This compact and method-independent representation of the electronic excitation provides a simple interpretation for the low-lying excited states of this set of molecules in terms of three different types of NTOs: "quinoid", "aromatic", and "π-bonded". When comparing with experiment, we found that only one molecule of this set is actually a high-spin triplet diradical. Others are almost closed-shell molecules with a very small contribution from a doubly excited configuration that only the spin-flip method could capture. The small amount of static correlation recovered by the spin-flip active space provides a linear relation between the first visible theoretical and experimental excitation energies among this set.

Isolation and Computational Studies of a Series of Terphenyl Substituted Diplumbynes with Ligand Dependent Lead-Lead Multiple-Bonding Character.

A series of formally triply bonded diplumbyne analogues of alkynes of the general formula ArPbPbAr (Ar = terphenyl ligand with different steric properties) was synthesized by two routes. All diplumbyne products were synthesized by a simple reduction of the corresponding Pb(II) halide precursor ArPb(Br) by DIBAL-H with yields in the range 8-48%. For one of the diplumbynes ArPri4PbPbArPri4 (ArPri4 = C6H3-2,6-(C6H3-2,6-Pri2)2) it was shown that reduction of ArPri4Pb(Br) using a magnesium(I) beta-diketiminate afforded a much improved yield in comparison (29 vs 8%) to that obtained by reduction with DIBAL-H. The more sterically crowded diplumbyne ArPri8PbPbArPri8 (ArPri8 = C6H-3,5-Pri2-2,6-(C6H2-2,4,6-Pri3)2) displayed a shortened Pb-Pb bond with a length of 3.0382(5) Å and wide Pb-Pb-C angles of 114.73(7)° and 116.02(6)° consistent with multiple-bond character with a bond order of up to 1.5. The others displayed longer metal-metal distances and narrower Pb-Pb-C angles that were consistent with a lower bond order that approached one. Computational studies of the diplumbynes yielded detailed insight of the unusual bonding and explained their similar electronic spectra arising from the flexibility of the C-Pb-Pb-C core in solution. Furthermore, the importance of London dispersion interactions for the stabilization of the diplumbynes was demonstrated.

Fully Automated Quantum-Chemistry-Based Computation of Spin-Spin-Coupled Nuclear Magnetic Resonance Spectra.

We present a composite procedure for the quantum-chemical computation of spin-spin-coupled 1 H NMR spectra for general, flexible molecules in solution that is based on four main steps, namely conformer/rotamer ensemble (CRE) generation by the fast tight-binding method GFN-xTB and a newly developed search algorithm, computation of the relative free energies and NMR parameters, and solving the spin Hamiltonian. In this way the NMR-specific nuclear permutation problem is solved, and the correct spin symmetries are obtained. Energies, shielding constants, and spin-spin couplings are computed at state-of-the-art DFT levels with continuum solvation. A few (in)organic and transition-metal complexes are presented, and very good, unprecedented agreement between the theoretical and experimental spectra was achieved. The approach is routinely applicable to systems with up to 100-150 atoms and may open new avenues for the detailed (conformational) structure elucidation of, for example, natural products or drug molecules.

Biomolecular Structure Information from High-Speed Quantum Mechanical Electronic Spectra Calculation.

A fully quantum mechanical (QM) treatment to calculate electronic absorption (UV-vis) and circular dichroism (CD) spectra of typical biomolecules with thousands of atoms is presented. With our highly efficient sTDA-xTB method, spectra averaged along structures from molecular dynamics (MD) simulations can be computed in a reasonable time frame on standard desktop computers. This way, nonequilibrium structure and conformational, as well as purely quantum mechanical effects like charge-transfer or exciton-coupling, are included. Different from other contemporary approaches, the entire system is treated quantum mechanically and neither fragmentation nor system-specific adjustment is necessary. Among the systems considered are a large DNA fragment, oligopeptides, and even entire proteins in an implicit solvent. We propose the method in tandem with experimental spectroscopy or X-ray studies for the elucidation of complex (bio)molecular structures including metallo-proteins like myoglobin.

Electronic Circular Dichroism of [16]Helicene With Simplified TD-DFT: Beyond the Single Structure Approach.

The electronic circular dichroism (ECD) spectrum of the recently synthesized [16]helicene and a derivative comprising two triisopropylsilyloxy protection groups was computed by means of the very efficient simplified time-dependent density functional theory (sTD-DFT) approach. Different from many previous ECD studies of helicenes, nonequilibrium structure effects were accounted for by computing ECD spectra on "snapshots" obtained from a molecular dynamics (MD) simulation including solvent molecules. The trajectories are based on a molecule specific classical potential as obtained from the recently developed quantum chemically derived force field (QMDFF) scheme. The reduced computational cost in the MD simulation due to the use of the QMDFF (compared to ab-initio MD) as well as the sTD-DFT approach make realistic spectral simulations feasible for these compounds that comprise more than 100 atoms. While the ECD spectra of [16]helicene and its derivative computed vertically on the respective gas phase, equilibrium geometries show noticeable differences, these are "washed" out when nonequilibrium structures are taken into account. The computed spectra with two recommended density functionals (ωB97X and BHLYP) and extended basis sets compare very well with the experimental one. In addition we provide an estimate for the missing absolute intensities of the latter. The approach presented here could also be used in future studies to capture nonequilibrium effects, but also to systematically average ECD spectra over different conformations in more flexible molecules. Chirality 28:365-369, 2016. © 2016 Wiley Periodicals, Inc.