Nature’s Chemical Signatures in Human Olfaction: A Foodborne Perspective for Future Biotechnology

The biocatalytic production of flavor naturals that determine chemosensory percepts of foods and beverages is an ever challenging target for academic and industrial research. Advances in chemical trace analysis and post‐genomic progress at the chemistry–biology interface revealed odor qualities of nature’s chemosensory entities to be defined by odorant‐induced olfactory receptor activity patterns. Beyond traditional views, this review and meta‐analysis now shows characteristic ratios of only about 3 to 40 genuine key odorants for each food, from a group of about 230 out of circa 10 000 food volatiles. This suggests the foodborn stimulus space has co‐evolved with, and roughly match our circa 400 olfactory receptors as best natural agonists. This perspective gives insight into nature’s chemical signatures of smell, provides the chemical odor codes of more than 220 food samples, and beyond addresses industrial implications for producing recombinants that fully reconstruct the natural odor signatures for use in flavors and fragrances, fully immersive interactive virtual environments, or humanoid bioelectronic noses.     

A Three‐Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors

Molecular‐dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V₂‐receptor (V₂R). Two of these, the vestibule and intermediate sites, block (antagonize) the receptor, and the third is the orthosteric activation (agonist) site. The contacts found for the orthosteric site satisfy all the requirements deduced from mutagenesis experiments. Metadynamics simulations for V₂R and its V_1aR‐analog give an excellent correlation with experimental binding free energies by assuming that the most stable binding site in the simulations corresponds to the experimental binding free energy in each case. The resulting three‐site mechanism separates agonists from antagonists and explains subtype selectivity.     

Accurate and Rigorous Prediction of the Changes in Protein Free Energies in a Large‐Scale Mutation Scan

The prediction of mutation‐induced free‐energy changes in protein thermostability or protein–protein binding is of particular interest in the fields of protein design, biotechnology, and bioengineering. Herein, we achieve remarkable accuracy in a scan of 762 mutations estimating changes in protein thermostability based on the first principles of statistical mechanics. The remaining error in the free‐energy estimates appears to be due to three sources in approximately equal parts, namely sampling, force‐field inaccuracies, and experimental uncertainty. We propose a consensus force‐field approach, which, together with an increased sampling time, leads to a free‐energy prediction accuracy that matches those reached in experiments. This versatile approach enables accurate free‐energy estimates for diverse proteins, including the prediction of changes in the melting temperature of the membrane protein neurotensin receptor 1.     

Computational Approach to Explore the B/A Junction Free Energy in DNA

Protein–DNA interactions induce conformational changes in DNA such as B‐ to A‐form transitions at a local level. Such transitions are associated with a junction free energy cost at the boundary of two different conformations in a DNA molecule. In this study, we performed umbrella sampling simulations to find the free energy values of the B–A transition at the dinucleotide and trinucleotide level of DNA. Using a combination of dinucleotide and trinucleotide free energy costs obtained from simulations, we calculated the B/A junction free energy. Our study shows that the B/A junction free energy is 0.52 kcal mol^?1 for the A‐philic GG step and 1.59 kcal mol^?1 for the B‐philic AA step. This observation is in agreement with experimentally derived values. After excluding junction effects, we obtained an absolute free energy cost for the B‐ to A‐form conversion for all the dinucleotide steps. These absolute free energies may be used for predicting the propensity of structural transitions in DNA.     

An estimation method of binding free energy in terms of ABEEMσπ/MM and continuum electrostatics fused into LIE method

A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. The linear interaction energy method is combined with atom‐bond electronegativity equalization method at σπ level Force field (fused into molecular mechanics) and generalized Born continuum model calculation of electrostatic solvation for the estimation of the absolute free energy of binding. The parameters of this method are calibrated by using a training set of 24 HIV‐1 protease–inhibitor complexes (PDB entry 1AAQ). A correlation coefficient of 0.93 was obtained with a root mean square deviation of 0.70 kcal mol^?1. This approach is further tested on seven inhibitor and protease complexes, and it provides small root mean square deviation between the calculated binding free energy and experimental binding free energy without reparametrization. By comparing the radii of gyration and the hydrogen bond distances between ligand and protein of three training model molecules, the consistent comparison result of binding free energy is obtained. It proves that this method of calculating the binding free energy with appropriate structural analysis can be applied to quickly assess new inhibitors of HIV‐1 proteases. To test whether the parameters of this method can apply to other drug targets, we have validated this method for the drug target cyclooxygenase‐2. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011     

辛味中药与嗅觉受体相互作用的分子模拟

采用分子模拟的方法, 在Schrdinger软件平台上, 用同源模建的方法构建了嗅觉受体OR1D2, OR7D4和OR51E1的三维结构模型. 运用分子动力学模块Desmond将与激动剂以及抑制剂分别对接的嗅觉受体复合物置于磷脂双膜中进行模拟. 最后将辛味中药的小分子分别对接到嗅觉受体中, 并与苦味中药的对接结果相对照, 依据实验结果, 讨论辛味中药发挥作用的分子机制. 该研究着重于同源模建、分子动力学和分子对接技术的综合应用, 探讨辛味中药化学成分与嗅觉受体的相互作用及其分子机理, 为从分子层面揭示辛味中药的药效物质基础提供帮助, 也为中药药性的研究提供了新的思路和方法.     

Comparison of two simulation methods to compute solvation free energies and partition coefficients

The thermodynamic integration (TI) and expanded ensemble (EE) methods are used here to calculate the hydration free energy in water, the solvation free energy in 1‐octanol, and the octanol‐water partition coefficient for a six compounds of varying functionality using the optimized potentials for liquid simulations (OPLS) all‐atom (AA) force field parameters and atomic charges. Both methods use the molecular dynamics algorithm as a primary component of the simulation protocol, and both have found wide applications in fields such as the calculation of activity coefficients, phase behavior, and partition coefficients. Both methods result in solvation free energies and 1‐octanol/water partition coefficients with average absolute deviations (AAD) from experimental data to within 4 kJ/mol and 0.5 log units, respectively. Here, we find that in simulations the OPLS‐AA force field parameters (with fixed charges) can reproduce solvation free energies of solutes in 1‐octanol with AAD of about half that for the solute hydration free energies using a extended simple point charge (SPC/E) model of water. The computational efficiency of the two simulation methods are compared based on the time (in nanoseconds) required to obtain similar standard deviations in the solvation free energies and 1‐octanol/water partition coefficients. By this analysis, the EE method is found to be a factor of nine more efficient than the TI algorithm. For both methods, solvation free energy calculations in 1‐octanol consume roughly an order of magnitude more CPU hours than the hydration free energy calculations. © 2012 Wiley Periodicals, Inc.     

Binding of Cationic and Neutral Phenanthridine Intercalators to a DNA Oligomer Is Controlled by Dispersion Energy: Quantum Chemical Calculations and Molecular Mechanics Simulations

Correlated ab initio as well as semiempirical quantum chemical calculations and molecular dynamics simulations were used to study the intercalation of cationic ethidium, cationic 5‐ethyl‐6‐phenylphenanthridinium and uncharged 3,8‐diamino‐6‐phenylphenanthridine to DNA. The stabilization energy of the cationic intercalators is considerably larger than that of the uncharged one. The dominant energy contribution with all intercalators is represented by dispersion energy. In the case of the cationic intercalators, the electrostatic and charge‐transfer terms are also important. The ΔG of ethidium intercalation to DNA was estimated at ?4.5 kcal mol^?1 and this value agrees well with the experimental result. Of six contributions to the final free energy, the interaction energy value is crucial. The intercalation process is governed by the non‐covalent stacking (including charge‐transfer) interaction while the hydrogen bonding between the ethidium amino groups and the DNA backbone is less important. This is confirmed by the evaluation of the interaction energy as well as by the calculation of the free energy change. The intercalation affects the macroscopic properties of DNA in terms of its flexibility. This explains the easier entry of another intercalator molecule in the vicinity of an existing intercalation site.     

A Membrane‐Free Redox Flow Battery with Two Immiscible Redox Electrolytes

Flexible and scalable energy storage solutions are necessary for mitigating fluctuations of renewable energy sources. The main advantage of redox flow batteries is their ability to decouple power and energy. However, they present some limitations including poor performance, short‐lifetimes, and expensive ion‐selective membranes as well as high price, toxicity, and scarcity of vanadium compounds. We report a membrane‐free battery that relies on the immiscibility of redox electrolytes and where vanadium is replaced by organic molecules. We show that the biphasic system formed by one acidic solution and one ionic liquid, both containing quinoyl species, behaves as a reversible battery without any membrane. This proof‐of‐concept of a membrane‐free battery has an open circuit voltage of 1.4 V with a high theoretical energy density of 22.5 Wh L⁻¹, and is able to deliver 90 % of its theoretical capacity while showing excellent long‐term performance (coulombic efficiency of 100 % and energy efficiency of 70 %).     

Enhanced Light‐Harvesting Capacity by Micellar Assembly of Free Accessory Chromophores and LH1‐like Antennas

Biohybrid light‐harvesting antennas are an emerging platform technology with versatile tailorability for solar‐energy conversion. These systems combine the proven peptide scaffold unit utilized for light harvesting by purple photosynthetic bacteria with attached synthetic chromophores to extend solar coverage beyond that of the natural systems. Herein, synthetic unattached chromophores are employed that partition into the organized milieu (e.g. detergent micelles) that house the LH1‐like biohybrid architectures. The synthetic chromophores include a hydrophobic boron‐dipyrrin dye (A1) and an amphiphilic bacteriochlorin (A2), which transfer energy with reasonable efficiency to the bacteriochlorophyll acceptor array (B875) of the LH1‐like cyclic oligomers. The energy‐transfer efficiencies are markedly increased upon covalent attachment of a bacteriochlorin (B1 or B2) to the peptide scaffold, where the latter likely acts as an energy‐transfer relay site for the (potentially diffusing) free chromophores. The efficiencies are consistent with a Förster (through‐space) mechanism for energy transfer. The overall energy‐transfer efficiency from the free chromophores via the relay to the target site can approach those obtained previously by relay‐assisted energy transfer from chromophores attached at distant sites on the peptides. Thus, the use of free accessory chromophores affords a simple design to enhance the overall light‐harvesting capacity of biohybrid LH1‐like architectures.     

Accurate free energy calculation along optimized paths

The path‐based methods of free energy calculation, such as thermodynamic integration and free energy perturbation, are simple in theory, but difficult in practice because in most cases smooth paths do not exist, especially for large molecules. In this article, we present a novel method to build the transition path of a peptide. We use harmonic potentials to restrain its nonhydrogen atom dihedrals in the initial state and set the equilibrium angles of the potentials as those in the final state. Through a series of steps of geometrical optimization, we can construct a smooth and short path from the initial state to the final state. This path can be used to calculate free energy difference. To validate this method, we apply it to a small 10‐ALA peptide and find that the calculated free energy changes in helix‐helix and helix‐hairpin transitions are both self‐convergent and cross‐convergent. We also calculate the free energy differences between different stable states of β‐hairpin trpzip2, and the results show that this method is more efficient than the conventional molecular dynamics method in accurate free energy calculation. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

The Flory mixing free energy: the effects of solute topology and monomer size

This note presents a lattice‐based derivation of the Flory free energy that does not invoke assumptions on the chain character of the solute. This derivation highlights two crucial features of the Flory free energy: (i) The mixing entropy S_mix is insensitive to the solute structural details. It depends only on the number of lattice sites occupied by the solute. (ii) In marked distinction, the mixing energy does vary with the topology of the solute, the monomer size and the dimensionality. Our discussion suggests re‐examination of the applicability of the Flory free energy to non‐polymeric solutions.     

Predicting the Switchable Screw Sense in Fluorene‐Based Polymers

A chirality‐switching free‐energy landscape was reconstructed on a 43‐mer of poly(9,9‐dioctylfluoren‐2,7‐diyl) (PDOF). The simulations were conducted on amorphous silica surface as well as in the vacuum phase for a single chain or for a group of sixteen chains. The achiral‐to‐chiral transition occurs only on amorphous silica (activation free‐energy 35 kcal mol^?1), where the enantiomeric (homochiral) basins are detected. This was supported by the experiments where effective chirality induction to PDOF using circularly polarized light (CPL) was attained only for a film deposited on a quartz glass and not for a solution or a suspension. These results indicate that interactions of PDOF with amorphous silica play a crucial role in chirality switching. Importance of chain assembling was also indicated. Theoretical ECD spectra of the enantiomeric basins containing a 5₁ helix reproduce the experimental spectra.     

Computational investigation of enantio‐ and regioselectivity of rhodium‐catalyzed asymmetric hydroformylation of vinyl formate with CHIRAPHOS‐type ligand

The potential energy profile for Rh‐catalyzed asymmetric hydroformylation of vinyl formate is mapped out using a nonlocal density functional method (B3LYP). This study focuses on the enantio‐ and regioselectivity of asymmetric hydroformylation. All the structures are optimized at the B3LYP/6‐31G(d,p) level(LANL2DZ(d) for Rh, P). As illustrated by computation, the olefin insertion step is irreversible because of higher activation free energy of the reverse reaction than that of forward reaction, so it is the determining step for both the regioselectivity and enantioselectivity in asymmetric hydroformylation. The lowest activation free energy in vinyl insertion is the path 2a → TS1a (ΔG^≠ = 47.92 kJ/mol), giving rise to the preferred product as (S)‐1‐formylenthyl formate. Throughout the catalytic cycle, the H₂ oxidative addition has the highest activation free energy, 77.24 kJ/mol, so it is the rate‐limiting step for the whole catalytic cycle. The calculation results are in agreement with many experiment investigations. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Metal‐Free Photocatalytic Hydrogenation Using Covalent Triazine Polymers

Photocatalytic hydrogenation of biomass‐derived organic molecules transforms solar energy into high‐energy‐density chemical bonds. Reported herein is the preparation of a thiophene‐containing covalent triazine polymer as a photocatalyst, with unique donor‐acceptor units, for the metal‐free photocatalytic hydrogenation of unsaturated organic molecules. Under visible‐light illumination, the polymeric photocatalyst enables the transformation of maleic acid into succinic acid with a production rate of about 2 mmol g^?1 h^?1, and furfural into furfuryl alcohol with a production rate of about 0.5 mmol g^?1 h^?1. Great catalyst stability and recyclability are also measured. Given the structural diversity of polymeric photocatalysts and their readily tunable optical and electronic properties, metal‐free photocatalytic hydrogenation represents a highly promising approach for solar energy conversion.     

Carbon‐Based Metal‐Free Catalysts for Electrocatalysis beyond the ORR

Besides their use in fuel cells for energy conversion through the oxygen reduction reaction (ORR), carbon‐based metal‐free catalysts have also been demonstrated to be promising alternatives to noble‐metal/metal oxide catalysts for the oxygen evolution reaction (OER) in metal–air batteries for energy storage and for the splitting of water to produce hydrogen fuels through the hydrogen evolution reaction (HER). This Review focuses on recent progress in the development of carbon‐based metal‐free catalysts for the OER and HER, along with challenges and perspectives in the emerging field of metal‐free electrocatalysis.     

A comparison of low and high activity precatalysts: Do the calculated energy barriers during the self‐metathesis reaction of 1‐Octene correlate with the precatalyst metathesis activity?

The self‐metathesis reaction of 1‐octene with several well‐known Grubbs‐type precatalysts and the new Z‐selective Grubbs precatalyst were studied with molecular modeling. The obtained Gibbs‐free energy values for all the steps during the productive metathesis of 1‐octene were compared to the values obtained for some low catalytic activity precatalysts. Determining how the Gibbs‐free energy values of highly active precatalysts compare to that of low catalytic activity precatalysts gave a deeper insight into the mechanism. The questionable correlation of the theoretically observed trends with those obtained experimentally does point to the need to be very cautious when making assumptions from theoretical results without a sufficiently large dataset. © 2014 Wiley Periodicals, Inc.     

Large‐Area,Free‐Standing,Two‐Dimensional Supramolecular Polymer Single‐Layer Sheets for Highly Efficient Electrocatalytic Hydrogen Evolution

The rational construction of covalent or noncovalent organic two‐dimensional nanosheets is a fascinating target because of their promising applications in electronics, membrane technology, catalysis, sensing, and energy technologies. Herein, a large‐area (square millimeters) and free‐standing 2D supramolecular polymer (2DSP) single‐layer sheet (0.7–0.9 nm in thickness), comprising triphenylene‐fused nickel bis(dithiolene) complexes has been readily prepared by using the Langmuir–Blodgett method. Such 2DSPs exhibit excellent electrocatalytic activities for hydrogen generation from water with a Tafel slope of 80.5 mV decade⁻¹ and an overpotential of 333 mV at 10 mA cm⁻², which are superior to that of recently reported carbon nanotube supported molecular catalysts and heteroatom‐doped graphene catalysts. This work is promising for the development of novel free‐standing organic 2D materials for energy technologies.     

Initial lamellar thickness dependency of recrystallization behavior of poly(4‐methyl‐1‐pentene)

The isothermal crystallization and subsequent melting process in semicrystalline poly(4‐methyl‐1‐pentene) were investigated via temperature‐dependent small‐ and wide‐angle X‐ray scattering and Flash DSC techniques. In a phase diagram of inversed crystalline lamellar thickness and temperature, the crystallization and melting lines can be described by two linear dependencies of different slopes and different limiting temperatures at infinite lamellar thickness. Upon subsequent heating, recrystallization lines with different slopes were observed for samples with different lamellar thickness, indicating changes in surface free energy difference between stabilized crystallites and mesomorphic phase. The surface free energy of native crystallites with extended‐chain conformation decreased with increasing lamellar thickness due to a more ordered surface region and less chain ends which changes cooperatively with mesomorphic phase. The surface free energy of stabilized crystallites remained unchanged for all lamellar thickness. Therefore, the recrystallization lines with different slopes are consequences of changes in surface free energy of mesomorphic phase. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56, 219–224     

On‐the‐fly reconstruction of free‐energy profiles using logarithmic mean‐force dynamics

Mean‐force dynamics (MFD), which is a fictitious dynamics for a set of collective variables on a potential of mean‐force, is a powerful algorithm to efficiently explore free‐energy landscapes. Recently, we have introduced logarithmic MFD (LogMFD) (Morishita et al., Phys. Rev. E 2012, 85, 066702) which overcomes difficulties encounterd in free‐energy calculations using standard approaches such as thermodynamic integration. Here, we present a guide to implementing LogMFD calculations paying attention to the practical issues in choosing the parameters in LogMFD. A primary focus is given to the effect of the parameters on the accuracy of the reconstructed free‐energy profiles. A recipe for reducing the errors due to energy dissipation is presented. We also demonstrate that multidimensional free‐energy landscapes can be reconstructed on‐the‐fly using LogMFD, which cannot be accomplished using any other free‐energy calculation techniques. © 2013 Wiley Periodicals, Inc.