Single-Electron Transfer in Frustrated Lewis Pair Chemistry

Frustrated Lewis pairs (FLPs) are well known for their ability to activate small molecules. Recent reports of radical formation within such systems indicate single-electron transfer (SET) could play an important role in their chemistry. Herein, we investigate radical formation upon reacting FLP systems with dihydrogen, triphenyltin hydride, or tetrachloro-1,4-benzoquinone (TCQ) both experimentally and computationally to determine the nature of the single-electron transfer (SET) events; that is, being direct SET to B(C₆F₅)₃ or not. The reactions of H₂ and Ph₃SnH with archetypal P/B FLP systems do not proceed via a radical mechanism. In contrast, reaction with TCQ proceeds via SET, which is only feasible by Lewis acid coordination to the substrate. Furthermore, SET from the Lewis base to the Lewis acid–substrate adduct may be prevalent in other reported examples of radical FLP chemistry, which provides important design principles for radical main-group chemistry.     

Development of a multi-objective coagulation system for long-term fouling control in dead-end ultrafiltration

In this paper, a multi-objective control system has been developed and experimentally tested. The multi-objective control system can be effectively used to control short-term fouling as well as long-term fouling. In an earlier study it was found that coagulant dosing in ultrafiltration can be used effectively to control the short-term fouling resistance during several sequential filtration cycles. To control long-term resistance increase during sequential chemical cleaning cycles, usually, in open-loop setting of the cleaning frequency or variables which influence the cleaning efficiency, such as, the cleaning time and the chemical composition are adjusted. Additional introductory experiments showed that changes in the coagulant dosing have a more pronounced effect on long-term fouling than changes in the usual applied variables. For this reason, it was decided to develop a closed-loop multi-objective controller where the coagulant dosing is used as the manipulated variable to accomplish both control objectives namely the fouling resistance over multiple filtration cycles (the short-term objective), as well as the irreversible fouling resistance over multiple chemical cleaning cycles (long-term objective). However, the controller is too slow to deal with temperature changes influencing the effectiveness of the coagulant dosing. To handle these influences a kind of gain scheduler should be included in the control algorithm.     

Improved evaluation of measurement uncertainty from sampling by inclusion of between-sampler bias using sampling proficiency testing

A realistic estimate of the uncertainty of a measurement result is essential for its reliable interpretation. Recent methods for such estimation include the contribution to uncertainty from the sampling process, but they only include the random and not the systematic effects. Sampling Proficiency Tests (SPTs) have been used previously to assess the performance of samplers, but the results can also be used to evaluate measurement uncertainty, including the systematic effects. A new SPT conducted on the determination of moisture in fresh butter is used to exemplify how SPT results can be used not only to score samplers but also to estimate uncertainty. The comparison between uncertainty evaluated within- and between-samplers is used to demonstrate that sampling bias is causing the estimates of expanded relative uncertainty to rise by over a factor of two (from 0.39% to 0.87%) in this case. General criteria are given for the experimental design and the sampling target that are required to apply this approach to measurements on any material.     

Biomimetic screening of class-B G protein-coupled receptors

The 41-amino acid peptide corticotropin releasing factor (CRF) is a major modulator of the mammalian stress response. Upon stressful stimuli, it binds to the corticotropin releasing factor receptor 1 (CRF(1)R), a typical member of the class-B G-protein-coupled receptors (GPCRs) and a prime target in the treatment of mood disorders. To chemically probe the molecular interaction of CRF with the transmembrane domain of its cognate receptor, we developed a high-throughput conjugation approach that mimics the natural activation mechanism of class-B GPCRs. An acetylene-tagged peptide library was synthesized and conjugated to an azide-modified high-affinity carrier peptide derived from the CRF C-terminus using copper-catalyzed dipolar cycloaddition. The resulting conjugates reconstituted potent agonists and were tested in situ for activation of the CRF(1) receptor in a cell-based assay. By use of this approach we (i) defined the minimal sequence motif that is required for full receptor activation, (ii) identified the critical functional groups and structure-activity relationships, (iii) developed an optimized, highly modified peptide probe with high potency (EC(50) = 4 nM) that is specific for the activation domain of the receptor, and (iv) probed the behavioral role of CRF receptors in living mice. The membrane recruitment by a high-affinity carrier enhanced the potency of the tethered peptides by >4 orders of magnitude and thus allowed the testing of very weak initial fragments that otherwise would have been inactive on their own. As no chromatography purification of the test peptides was necessary, a substantial increase in screening throughput was achieved. Importantly, the peptide conjugates can be used to probe the endogenous receptor in its native environment in vivo.     

Simple Hamiltonians which exhibit drastic failures by variational determination of the two-particle reduced density matrix with some well known N-representability conditions

Calculations on small molecular systems indicate that the variational approach employing the two-particle reduced density matrix (2-RDM) as the basic unknown and applying the P, Q, G, T1, and T2 representability conditions provides an accuracy that is competitive with the best standard ab initio methods of quantum chemistry. However, in this paper we consider a simple class of Hamiltonians for which an exact ground state wave function can be written as a single Slater determinant and yet the same 2-RDM approach gives a drastically nonrepresentable result. This shows the need for stronger representability conditions than the mentioned ones.     

Therapeutic Fc‐fusion proteins: Current analytical strategies

Fc‐Fusion proteins represent a successful class of biopharmaceutical products, with already 13 drugs approved in the European Union and United States as well as three biosimilar versions of etanercept. Fc‐Fusion products combine tailored pharmacological properties of biological ligands, together with multiple functions of the fragment crystallizable domain of immunoglobulins. There is a great diversity in terms of possible biological ligands, including the extracellular domains of natural receptors, functionally active peptides, recombinant enzymes, and genetically engineered binding constructs acting as cytokine traps. Due to their highly diverse structures, the analytical characterization of Fc‐Fusion proteins is far more complex than that of monoclonal antibodies and requires the use and development of additional product‐specific methods over conventional generic/platform methods. This can be explained, for example, by the presence of numerous sialic acids, leading to high diversity in terms of isoelectric points and complex glycosylation profiles including multiple N‐ and O‐linked glycosylation sites. In this review, we highlight the wide range of analytical strategies used to fully characterize Fc‐fusion proteins. We also present case studies on the structural assessment of all commercially available Fc‐fusion proteins, based on the features and critical quality attributes of their ligand‐binding domains.     

Ab initio based potential energy surfaces and Franck-Condon analysis of ionization thresholds of cyclic-C3H and linear-C3H

We report a Franck-Condon analysis in reduced dimensionality of the ionization thresholds of linear(l)-C3H and cyclic(c)-C3H using MP2-based potential energy surfaces and CCSD(T)/aug-cc-pVTZ calculations of electronic energies at selected geometries. The potential energy surfaces are fits to tens of thousands of MP2/aug-cc-pVTZ energies for the neutral and cation systems. These fits properly describe the invariance of the potential with respect to all permutations of the three C atoms. The realism of the potential surfaces is assessed by comparing stationary-point structures, energies, and normal-mode frequencies with previous high-level ab initio calculations. Several key vibrational modes in this ionization process are located at saddle points and so a numerical approach to obtain the Franck-Condon factors for those modes is done. On the basis of this analysis combined with a simple harmonic treatment of the energies of the remaining modes and key electronic energy differences obtained with CCSD(T)/aug-cc-pVTZ calculations, we find the threshold ionization energy of l-C3H to be 9.06 eV and for c-C3H we estimate the threshold to be in the range 9.70-9.76 eV. We estimate these values are accurate to within +/-0.05 eV.     

On the short-time limit of ring polymer molecular dynamics

We examine the short-time accuracy of a class of approximate quantum dynamical techniques that includes the centroid molecular dynamics (CMD) and ring polymer molecular dynamics (RPMD) methods. Both of these methods are based on the path integral molecular dynamics (PIMD) technique for calculating the exact static equilibrium properties of quantum mechanical systems. For Kubo-transformed real-time correlation functions involving operators that are linear functions of positions or momenta, the RPMD and (adiabatic) CMD approximations differ only in the choice of the artificial mass matrix of the system of ring polymer beads that is employed in PIMD. The obvious ansatz for a general method of this type is therefore to regard the elements of the PIMD (or Parrinello-Rahman) mass matrix as an adjustable set of parameters that can be chosen to improve the accuracy of the resulting approximation. We show here that this ansatz leads uniquely to the RPMD approximation when the criterion that is used to select the mass matrix is the short-time accuracy of the Kubo-transformed correlation function. In particular, we show that the leading error in the RPMD position autocorrelation function is O(t(8)) and the error in the velocity autocorrelation function is O(t(6)), for a general anharmonic potential. The corresponding errors in the CMD approximation are O(t(6)) and O(t(4)), respectively.     

Potential energy surface and MULTIMODE vibrational analysis of C2H3+

A full dimensional, ab initio-based semiglobal potential energy surface for C(2)H(3) (+) is reported. The ab initio electronic energies for this molecule are calculated using the spin-restricted, coupled cluster method restricted to single and double excitations with triples corrections [RCCSD(T)]. The RCCSD(T) method is used with the correlation-consistent polarized valence triple-zeta basis augmented with diffuse functions (aug-cc-pVTZ). The ab initio potential energy surface is represented by a many-body (cluster) expansion, each term of which uses functions that are fully invariant under permutations of like nuclei. The fitted potential energy surface is validated by comparing normal mode frequencies at the global minimum and secondary minimum with previous and new direct ab initio frequencies. The potential surface is used in vibrational analysis using the "single-reference" and "reaction-path" versions of the code MULTIMODE.     

Quasiclassical trajectory calculations of the reaction C+C2H2-->l-C3H, c-C3H+H, C3+H2 using full-dimensional triplet and singlet potential energy surfaces

Full-dimensional, density functional theory (B3LYP/6-311g(d,p))-based potential energy surfaces (PESs) are reported and used in quasi-classical calculations of the reaction of C with C(2)H(2). For the triplet case, the PES spans the region of the reactants, the complex region (with numerous minima and saddle points) and the products, linear(l)-C(3)H+H, cyclic(c)-C(3)H+H and c-(3)C(3)+H(2). For the singlet case, the PES describes the complex region and products l-C(3)H+H, c-C(3)H+H and l-(1)C(3)+H(2). The PESs are invariant under permutation of like nuclei and are fit to tens of thousands of electronic energies. Energies and harmonic frequencies of the PESs agree well the DFT ones for all stationary points and for the reactant and the products. Dynamics calculations on the triplet PES find both l-C(3)H and c-C(3)H products, with l-C(3)H being dominant at the energies considered. Limited unimolecular reaction dynamics on the singlet PES find both products in comparable amounts as well as the C(3)+H(2) product.