One of the most basic and unresolved puzzles in the chemistry of vision is the mechanism regulating the absorbance of the visual photoreceptors. Rhodopsin, the rod pigment that mediates black/white vision in the human eye, absorbs at 498 nm; the three cone pigments responsible for trichromatic (color) vision absorb at 425, 530, and 560 nm, respectively. Since the chromophore in these receptors is the same protonated Schiff base of 11-cis-retinal (pSb11), the spectra of these pigments are clearly a function of the protein environment the chromophore "sees"; in other words, the spectra are tuned by the protein. [1] Three mechanisms are generally agreed to be involved in spectral tuning: 1) distortion of the chromophore as a result of steric interactions with the protein binding pocket; 2) interaction of the chromophore with the counterion balancing its positive charge; and 3) interaction of the chromophore with the remaining polar residues of the amino acids lining the binding pocket. However, the importance of these contributions could not be assessed quantitatively as long as realistic structures of the visual pigments were not available. This changed with the first X-ray crystal structure of rhodopsin, [2] now solved down to 2.2-resolution, [3] which made it possible to study the chromophore including its environment with high-quality quantum-mechanical methods. [4][5][6][7] Despite considerable insights gained from these studies, fundamental questions remain, in particular to what extent the amino acid residues of the binding pocket affect the spectrum of the chromophore.Very recently the absorption cross section of pSb11 in the gas phase was determined by analyzing fragments of photochemically excited ions.[8] Devoid of the restraining forces and charges of the protein environment, the chromophore in the gas phase or vacuum appears tailor-made for high-level quantum-mechanical calculations. It also presents a welldefined point of reference for the analysis of spectral tuning in rhodopsin. Using multiconfigurational perturbation theory we have been able to reproduce the experimental absorption maximum of the bare rhodopsin chromophore (610 nm) with high accuracy.[9] Employing the same theoretical platform we show in the following that the three contributions discussed above add up quantitatively to the experimentally observed spectral shift of the chromophore on going from the vacuum to the rhodopsin molecule. By far the largest contributor to the shift is the counterion, while the role of the polar amino acid residues of the protein pocket, contrary to general consensus, is limited to modulating the spectrum.The calculations were performed on three pSb11 model systems derived from the SCC-DFTB-refined [10] geometry of the rhodopsin binding pocket with 2.2-resolution shown in Figure 1, and they increasingly reflect the influence of the protein. Starting with the optimized vacuum structure pSb11 vac described earlier, [9] changes in the geometry corresponding to the calculated rhodopsin structure were added whic...

We elucidate local packing motifs and dynamical order parameters in a perylene tetracarboxydiimide derivative (C(8,7)-PDI), one of the most promising candidates for rationally designed, self-assembling, and self-healing molecular wires. Spectroscopic fingerprints obtained from solid-state NMR spectroscopy are interpreted by means of first-principles calculations and molecular dynamics simulations. The interplay of steric repulsion, H bonding, and pi-pi packing effects leads to a specific relative molecular pitch angle of approximately 35 +/- 10 degrees between successive molecules in the stack. Dynamical order parameters, determined from NMR sideband patterns as a measure of molecular motion, yield values of S approximately = 1.0 in the core of the columnar stack, corresponding to an almost frozen molecular dynamics at ambient temperature. This rigidity is compatible with characteristic intermolecular distances obtained from dipolar couplings between specific hydrogens via double-quantum NMR experiments and further supported by ab initio calculations.

The synthesis of perylene 3,4:9,10-tetracarboxylic acid bisimides (PBIs) dendronized with first-generation dendrons containing 0 to 4 methylenic units (m) between the imide group and the dendron, (3,4,5)12G1-m-PBI, is reported. Structural analysis of their self-organized arrays by DSC, X-ray diffraction, molecular modeling, and solid-state (1)H NMR was carried out on oriented samples with heating and cooling rates of 20 to 0.2 °C/min. At high temperature, (3,4,5)12G1-m-PBI self-assemble into 2D-hexagonal columnar phases with intracolumnar order. At low temperature, they form orthorhombic (m = 0, 2, 3, 4) and monoclinic (m = 1) columnar arrays with 3D periodicity. The orthorhombic phase has symmetry close to hexagonal. For m = 0, 2, 3, 4 ,they consist of tetramers as basic units. The tetramers contain a pair of two molecules arranged side by side and another pair in the next stratum of the column, turned upside-down and rotated around the column axis at different angles for different m. In contrast, for m = 1, there is only one molecule in each stratum, with a four-strata 2(1) helical repeat. All molecules face up in one column, and down in the second column, of the monoclinic cell. This allows close and extended π-stacking, unlike in the disruptive up-down alteration from the case of m = 0, 2, 3, 4. Most of the 3D structures were observed only by cooling at rates of 1 °C/min or less. This complex helical self-assembly is representative for other classes of dendronized PBIs investigated for organic electronics and solar cells.

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/ deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and 13 C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d 30 lacks the 1,380-to 1,550-cm −1 IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.olfaction | isotopomers | cyclopentadecanone | muscone | electron transfer I n 1870, the British physician William Ogle wrote: "As in the eye and the ear the sensory impression is known to result not from the contact of material particles given off by the object seen or heard, but from waves or undulations of the ether or the air, one cannot but suspect that the same may be true in the remaining sense, and that the undulatory theory of smell. . . [may be] the true one" (1, 2). Of the 29 different "theories of odour" listed in the 1967 edition of The Chemical Senses (3), nine associate odor with vibrations, particularly those theories championed by Dyson (4, 5) and Wright (6-8). However, the premise that olfaction involves detection of vibrational frequencies of odorants remains highly speculative because neither the structures of the odorant receptors (ORs) nor the binding sites or the activation mechanisms triggered upon odorant binding to ORs have been established. In 1996-1997, Turin (9-12) elaborated on the undulatory theory of smell, as considered in more detail below, and suggested that a mechanism analogous to inelastic electron tunneling spectroscopy (13) may be involved, where tunneling electrons in the receptor probe the vibrational frequencies of odorants. In 2013, Gane et al. (14) In judging the plausibility...

We have studied the wavelength dependence of retinal Schiff base absorbencies on the protonation state of the chromophore at the multiconfigurational level of theory using second order perturbation theory (CASPT2) within an atomic natural orbital basis set on MP2 optimized geometries. Quantitative agreement between calculated and experimental absorption maxima was obtained for protonated and deprotonated Schiff bases of all-trans- and 11-cis-retinal and intermediate states covering a wavelength range from 610 to 353 nm. These data will be useful as reference points for the calibration of more approximate schemes.

By comparing the results from a hybrid quantum mechanics/molecular mechanics (QM/MM) method (SORCI+Q//B3LYP/6-31G*:Amber) between the vertebrate (bovine) and invertebrate (squid) visual pigments, the mechanism of molecular rearrangements, energy storage and origin of the bathochromic shift accompanying the transformation of rhodopsin to bathorhodopsin have been evaluated. The analysis reveals that, in the presence of an unrelaxed binding site, bathorhodopsin was found to carry almost 27 kcal·mol−1 energy in both the visual pigments and absorb (λmax) at 528 nm in bovine and 554 nm in squid. However, when the residues within 4.0Å radius of the retinal are relaxed during the isomerization event, almost ~16 kcal·mol−1 energy is lost in squid compared to only ~8 kcal·mol−1 in bovine. Loss of larger amount of energy in squid is attributed to the presence of a flexible binding site compared to a rigid binding site in bovine. Structure of the squid bathorhodopsin is characterized by formation of a direct H-bond between the Schiff base and Asn87.

Eyes gather information and color forms an extremely important component of the information, more so in the case of animals to forage and navigate within their immediate environment. By using the ONIOM (QM/MM) method, we report a comprehensive theoretical analysis of the structure and molecular mechanism of spectral tuning of monkey-red and green-sensitive visual pigments. We show that, interaction of retinal with three hydroxyl-bearing amino acids near the β-ionone ring part of the retinal in opsin, A164S, F261Y and A269T, increases the electron delocalization, decreases the BLA of the retinal and leads to variation in the wavelength of maximal absorbance in the red- and green-sensitive visual pigments. Based on the analysis, we propose the “OH-site” rule for seeing red and green. This rule is also shown to account for the spectral shifts obtained from hydroxyl-bearing amino acids near the Schiff base in different visual pigments: at site 292 (A292S, A292Y, and A292T) in bovine and at site 111 (Y111) in squid opsins. Therefore, the OH-site rule is shown to be site-specific and not pigment-specific and thus can be used for tracking spectral shifts in any visual pigment.

Interest is growing in the use of macrocycles in pharmaceutical discovery. Macrocylization may provide a gateway to an expanded chemical space for small-molecule drug discovery, and this could be beneficial in prosecuting difficult targets, e.g., protein–protein interactions. Most, but not all, macrocycle drugs are derived from natural products. Studies on synthetic drug-like small-molecule macrocycles are limited, and our current understanding of macrocycle drugs is similarly limited. Following some background discussion, we review several examples of the structure-based design of synthetic macrocycles. Our opinion is that in conformationally suitable systems macrocycles are an analog class worthy of consideration. We then summarize an approach for the initial evaluation of molecules as candidates for macrocyclization.