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Studies of these phenomena call for characterization of Berry phase or curvature which is largely limited to theory, and a few measurements in optical lattices. We show that the two manifestations of broken inversion symmetry in solids lead to perpendicular or parallel polarization of even harmonics with respect to the driving field. Using semiclassical transport theory, we retrieve the Berry curvature from spectra measured in perpendicular polarization, the results being supported by ab initio calculation.
Our work demonstrates an approach for the direct measurement of Berry curvature in solids, which could serve as a benchmark for theoretical studies. Here, we report that amyloids composed of short peptides can direct the sequence-selective, regioselective and stereoselective condensation of amino acids. Furthermore, the templating reaction is stable over a wide range of pH 5. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG.
X-ray crystallography was used alongside NMR at kHz MAS with sedimented soluble protein to explore possibilities for refining the compound as an allosteric modulator. Proton-detected MAS NMR experiments on fully protonated [13C,15N]-labeled FcRnECD yielded ligand-induced chemical-shift perturbations CSPs for residues in the binding pocket and allosteric changes close to the interface of the two receptor heterodimers present in the asymmetric unit as well as potentially in the albumin interaction site.
Our investigation establishes a method to characterize structurally small molecule binding to nondeuterated large proteins by NMR, even in their glycosylated form, which may prove highly valuable for structure-based drug discovery campaigns. In the present review, laser fields are so strong that they become part of the electronic potential, and sometimes even dominate the Coulomb contribution.
This manipulation of atomic potentials and of the associated states and bands finds fascinating applications in gases and solids, both in the bulk and at the surface. Ionization and, in particular, ionization through the interaction with light play an important role in fundamental processes in physics, chemistry, and biology.
In recent years, we have seen tremendous advances in our ability to measure the dynamics of photo-induced ionization in various systems in the gas, liquid, or solid phase. In this review, we will define the parameters used for quantifying these dynamics. We give a brief overview of some of the most important ionization processes and how to resolve the associated time delays and rates.
With regard to time delays, we ask the question: how long does it take to remove an electron from an atom, molecule, or solid? With regard to rates, we ask the question: how many electrons are emitted in a given unit of time? We present state-of-the-art results on ionization and photoemission time delays and rates. Our review starts with the simplest physical systems: the attosecond dynamics of single-photon and tunnel ionization of atoms in the gas phase. We then extend the discussion to molecular gases and ionization of liquid targets. Finally, we present the measurements of ionization delays in femto- and attosecond photoemission from the solid—vacuum interface.
We review several methods for computing kinetic isotope effects in chemical reactions including semiclassical and quantum instanton theory. The absolute rate constants computed with the semiclassical instanton method both using on-the-fly electronic structure calculations and fitted potential-energy surfaces are also compared directly with exact quantum dynamics results.
The error inherent in the instanton approximation is found to be relatively small and similar in magnitude to that introduced by using fitted surfaces. The kinetic isotope effect computed by the quantum instanton is even more accurate, and although it is computationally more expensive, the efficiency can be improved by path-integral acceleration techniques. We also test a simple approach for designing potential-energy surfaces for the example of proton transfer in malonaldehyde. The tunneling splittings are computed, and although they are found to deviate from experimental results, the ratio of the splitting to that of an isotopically substituted form is in much better agreement.
We discuss the strengths and limitations of the potential-energy surface and based on our findings suggest ways in which it can be improved. Nucleotidyl cyclases, including membrane-integral and soluble adenylyl and guanylyl cyclases, are central components in a wide range of signaling pathways. These proteins are architecturally diverse, yet many of them share a conserved feature, a helical region that precedes the catalytic cyclase domain. The role of this region in cyclase dimerization has been a subject of debate. Although mutations within this region in various cyclases have been linked to genetic diseases, the molecular details of their effects on the enzymes remain unknown.
Here, we report an X-ray structure of the cytosolic portion of the membrane-integral adenylyl cyclase Cya from Mycobacterium intracellulare in a nucleotide-bound state. The helical domains of each Cya monomer form a tight hairpin, bringing the two catalytic domains into an active dimerized state. Mutations in the helical domain of Cya mimic the disease-related mutations in human proteins, recapitulating the profiles of the corresponding mutated enzymes, adenylyl cyclase-5 and retinal guanylyl cyclase Our experiments with full-length Cya and its cytosolic domain link the mutations to protein stability, and the ability to induce an active dimeric conformation of the catalytic domains.
Sequence conservation indicates that this domain is an integral part of cyclase machinery across protein families and species. Our study provides evidence for a role of the helical domain in establishing a catalytically competent dimeric cyclase conformation. Our results also suggest that the disease-associated mutations in the corresponding regions of human nucleotidyl cyclases disrupt the normal helical domain structure.
The transfer of charge at the molecular level plays a fundamental role in many areas of chemistry, physics, biology and materials science.
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Marcus, charge transfer is still a very active field of research. An important recent impetus comes from the ability to resolve ever faster temporal events, down to the attosecond time scale. Such a high temporal resolution now offers the possibility to unravel the most elementary quantum dynamics of both electrons and nuclei that participate in the complex process of charge transfer. This review covers recent research that addresses the following questions.
Can we reconstruct the migration of charge across a molecule on the atomic length and electronic time scales? Can we use strong laser fields to control charge migration? Can we temporally resolve and understand intramolecular charge transfer in dissociative ionization of small molecules, in transition-metal complexes and in conjugated polymers? Can we tailor molecular systems towards specific charge-transfer processes? What are the time scales of the elementary steps of charge transfer in liquids and nanoparticles? It has been suggested that the origin of regio- and stereoselectivity in Michael additions of pyrrolidine enamines is achieved by thermodynamic rather than kinetic control through distinct conformational preferences of the enamines.
We assess this proposal by elaboration of a computational protocol that warrants sufficient accuracy. The small energy differences between the conformers necessitate a high accuracy of the electronic structure method which, in addition, must allow for computationally feasible calculations of a large number of conformers. Our protocol is based on density functional theory which we validated against explicitly correlated coupled cluster theory.
The results are in agreement with the available experimental data, but illustrate that conformational preferences determined for one enamine are not readily transferable to other types of enamines. We found that an appropriate conformational sampling is inevitable to arrive at meaningful conclusions.
Most prominently, s-cis and strans conformers are similarly stable for aldehyde- and ketone-derived enamines. The regio- and stereoselectivity in Michael additions of pyrrolidine-derived enamines can not be explained by pronounced stability differences of the enamine isomers and conformers in general, disproving the thermodynamic-control hypothesis. The elucidation of the origin of regio- and stereoselectivity requires further theoretical investigations of the elementary steps of Michael additions. The Einstein-Podolski-Rosen paradox highlights several strange properties of quantum mechanics including the super position of states, the non locality and its limitation to determine an experiment only statistically.
It is further assumed that time is a single variable, that the quantum mechanics time evolution and the classical physics discrete time evolution are coherent to each other, and that the precision of the start of the experiment and of the measurement time point are much less than t. Although often depicted as rigid structures, proteins are highly dynamic systems, whose motions are essential to their functions. Despite this, it is difficult to investigate protein dynamics due to the rapid timescale at which they sample their conformational space, leading most NMR-determined structures to represent only an averaged snapshot of the dynamic picture.
While NMR relaxation measurements can help to determine local dynamics, it is difficult to detect translational or concerted motion, and only recently have significant advances been made to make it possible to acquire a more holistic representation of the dynamics and structural landscapes of proteins. Here, we briefly revisit our most recent progress in the theory and use of exact nuclear Overhauser enhancements eNOEs for the calculation of structural ensembles that describe their conformational space.
New developments are primarily targeted at increasing the number and improving the quality of extracted eNOE distance restraints, such that the multi-state structure calculation can be applied to proteins of higher molecular weights. We then review the implications of the exact NOE to the protein dynamics and function of cyclophilin A and the WW domain of Pin1, and finally discuss our current research and future directions.
The new cooperative catalysis has important implications for the combination of non-metallic main-group catalysis with photocatalysis. The unknown influence of inelastic and elastic scattering of slow electrons in water has made it difficult to clarify the role of the solvated electron in radiation chemistry and biology. We combine accurate scattering simulations with experimental photoemission spectroscopy of the hydrated electron in a liquid water microjet, with the aim of resolving ambiguities regarding the influence of electron scattering on binding energy spectra, photoelectron angular distributions, and probing depths.
The scattering parameters used in the simulations are retrieved from independent photoemission experiments of water droplets. For the ground-state hydrated electron, we report genuine values devoid of scattering contributions for the vertical binding energy and the anisotropy parameter of 3. Our probing depths suggest that even vacuum ultraviolet probing is not particularly surface-selective.
Our work demonstrates the importance of quantitative scattering simulations for a detailed analysis of key properties of the hydrated electron. A significant problem with paramagnetic tags attached to proteins and nucleic acids is their conformational mobility.
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Each tag is statistically distributed within a volume between 5 and 10 Angstroms across; structural biology conclusions from NMR and EPR work are necessarily diluted by this uncertainty. The problem is solved in electron spin resonance, but remains open in the other major branch of paramagnetic resonance — pseudocontact shift PCS NMR spectroscopy, where structural biologists have so far been reluctantly using the point paramagnetic centre approximation.
Here we describe a new method for extracting probability densities of lanthanide tags from PCS data. The method relies on Tikhonov-regularised 3D reconstruction and opens a new window into biomolecular structure and dynamics because it explores a very different range of conditions from those accessible to double electron resonance work on paramagnetic tags: a room-temperature solution rather than a glass at cryogenic temperatures. The wealth of high-quality pseudocontact shift data accumulated by the biological magnetic resonance community over the last 30 years, and so far only processed using point models, could now become a major source of useful information on conformational distributions of paramagnetic tags in biomolecules.
Interestingly, these fibrils often do not obtain one single structure but rather show different morphologies, so-called polymorphs. This comparison reveals secondary structural differences between the two polymorphs suggesting that the two polymorphisms can be classified as segmental polymorphs. Factors affecting the performance of 1H heteronuclear decoupling sequences for magic-angle spinning MAS NMR spectroscopy of organic solids are explored, as observed by time constants for the decay of nuclear magnetisation under a spin-echo math formula.
By using a common protocol over a wide range of experimental conditions, including very high magnetic fields and very high radio-frequency RF nutation rates, decoupling performance is observed to degrade consistently with increasing magnetic field. Increasing RF nutation rates dramatically improve robustness with respect to RF offset, but the performance of phase-modulated sequences degrades at the very high nutation rates achievable in microcoils as a result of RF transients.
The insights gained provide better understanding of the factors limiting decoupling performance under different conditions, and the high values of math formula observed which generally exceed previous literature values provide reference points for experiments involving spin magnetisation refocussing, such as 2D correlation spectra and measuring small spin couplings. We analyze resonance Raman spectra of the nucleobase uracil in the short-time approximation calculated with multiconfigurational methods.
We discuss the importance of static electron correlation by means of density-matrix renormalization group self-consistent field DMRG-SCF calculations. With a parameter-free multireference perturbation theory approach at hand, the latter allows us to efficiently describe static and dynamic correlation in large molecular systems. We first assess, in a study of a heme model, the accuracy of the strongly and partially contracted variant of CD-DMRG-NEVPT2 before embarking on resolving a controversy about the spin ground state of a cobalt tropocoronand complex.
Due to their very nature, ultrafast phenomena are often accompanied by the occurrence of nonadiabatic effects. In this review, we give an overview of different nonadiabatic processes that manifest themselves in electronic and nuclear dynamics ranging from the nonadiabatic phenomena taking place during tunnel ionization of atoms in strong laser fields to the radiationless relaxation through conical intersections and the nonadiabatic coupling of vibrational modes and discuss the computational approaches that have been developed to describe such phenomena.
These methods range from the full solution of the combined nuclear-electronic quantum problem to a hierarchy of semiclassical approaches and even purely classical frameworks. The power of these simulation tools is illustrated by representative applications and the direct confrontation with experimental measurements performed in the National Centre of Competence for Molecular Ultrafast Science and Technology.
Formylglycine-generating enzyme FGE is an O2-utilizing oxidase that converts specific cysteine residues of client proteins to formylglycine. These findings establish FGE as a novel type of copper enzyme. Hyperpolarized silicon particles have been shown to exhibit long spin-lattice relaxation times at room temperature, making them interesting as novel MRI probes. A maximum polarization of The presence of unpaired electrons polarizing agents is crucial for DNP, but it has drawbacks such as leading to faster nuclear spin relaxation, or even reaction with the substrate under investigation.
The latter can be a particular problem for heterogeneous catalysts. Here, we present a series of carbosilane-based dendritic polarizing agents, in which the bulky dendrimer can reduce the interaction between the solid surface and the free radical. Inclusions first appear in olfactory bulb and enteric neurons then in ascendant neuroanatomical interconnected areas, and finally, in late stages of the disease, Lewy bodies are observed in a substantia nigra pars compacta with clear signs of neuronal loss.
We present a detailed analysis of various tensor network parameterizations within the complete graph tensor network states CGTNS approach. For this we devise three different strategies. The first relies solely on 3-site correlators and the second on 3-site correlators added on top of the 2-site correlator ansatz. To avoid an inflation of the variational space introduced by higher-order correlators, we limit the number of higher-order correlators to the most significant ones in the third strategy.
Approaches for the selection of these most significant correlators are discussed. The sextet and doublet spin states of the spin-crossover complex manganocene serve as a numerical test case. In general, the CGTNS scheme achieves a remarkable accuracy for a significantly reduced size of the variational space. The advantages, drawbacks, and limitations of all CGTNS parameterizations investigated are rigorously discussed.
Nanoscale distance measurements by pulse dipolar Electron paramagnetic resonance EPR spectroscopy allow new insights into the structure and dynamics of complex biopolymers. Application of pulsed double electron—electron resonance provided spin—spin distance distribution, which agrees well with the results of molecular dynamics MD calculations.
Functional recovery from central neurotrauma, such as spinal cord injury, is limited by myelin-associated inhibitory proteins. Q-band and X-band pulsed electron paramagnetic resonance spectroscopic methods EPR in the solid state were employed to refine the parameters characterizing the anisotropic interactions present in six nitroxide radicals prepared by N,N addition of NO to various borane-phosphane frustrated Lewis pairs FLPs.
It was previously shown that continuous-wave spectra measured at X-band frequency 9. On the other hand, the X-band electron spin echo envelope modulation ESEEM and hyperfine sublevel correlation HYSCORE spectra are completely dominated by the nuclear hyperfine coupling to the 11B nuclei, allowing a selective determination of their interaction parameters. In the present work this analysis has been further validated by temperature dependent ESEEM measurements. Based on these new results, we report here high-accuracy and precision data of the EPR spin Hamiltonian parameters measured on six FLP-NO radical species embedded in their corresponding hydroxylamine host structures.
While the ESEEM spectra at Q-band frequency turn out to be very complex due to the multinuclear contribution to the overall signal in the HYSCORE experiment the extension over two dimensions renders a better discrimination between the different nuclear species, and the signals arising from hyperfine coupling to 10B, 11B, 14N and 31P nuclei can be individually analyzed. The P2X7 receptor is a member of the P2X family of ligand-gated ion channels.
A single-nucleotide polymorphism leading to a glutamine Gln by arginine Arg substitution at codon of the purinergic P2X7 receptor P2X7R has been associated with mood disorders. No change in function loss or gain has been described for this SNP so far. Here we show that although the P2X7R-GlnArg variant per se is not compromised in its function, co-expression of wild-type P2X7R with P2X7R-GlnArg impairs receptor function with respect to calcium influx, channel currents and intracellular signaling in vitro. Specific silencing of either the normal or polymorphic variant rescues the heterozygous loss of function phenotype and restores normal function.
The described loss of function due to co-expression, unique for mutations in the P2RX7 gene so far, explains the mechanism by which the P2X7R-GlnArg variant affects the normal function of the channel and may represent a mechanism of action for other mutations. A series of 37 dinitroxide biradicals have been prepared and their performance studied as polarizing agents in cross-effect DNP NMR experiments at 9. We observe that in this regime the DNP performance is strongly correlated with the substituents on the polarizing agents, and electron and nuclear spin relaxation times, with longer relaxation times leading to better enhancements.
We also observe that deuteration of the radicals generally leads to better DNP enhancement but with longer build-up time. One of the new radicals introduced here provides the best performance obtained so far under these conditions. Directed cell movement involves spatial and temporal regulation of the cortical microtubule Mt and actin networks to allow focal adhesions FAs to assemble at the cell front and disassemble at the rear. Mts are known to associate with FAs, but the mechanisms coordinating their dynamic interactions remain unknown.
Cells lacking CRL3KLHL21 activity or expressing a non-ubiquitylatable EB1 mutant protein are unable to migrate and exhibit strong defects in FA dynamics, lamellipodia formation and cortical plasticity. Our study thus reveals an important mechanism to regulate cortical dynamics during cell migration that involves ubiquitylation of EB1 at focal adhesions. Nanofocusing of electromagnetic radiation inside aerosols plays a crucial role in their absorption behaviour, since the radiation flux inside the droplet strongly affects the activation rate of photochemically active species.
However, size-dependent nanofocusing effects in the photokinetics of small aerosols have escaped direct observation due to the inability to measure absorption signatures from single droplets. Here we show that photoacoustic measurements on optically trapped single nanodroplets provide a direct, broadly applicable method to measure absorption with attolitre sensitivity. We demonstrate for a model aerosol that the photolysis is accelerated by an order of magnitude in the sub-micron to micron size range, compared with larger droplets.
The versatility of our technique promises broad applicability to absorption studies of aerosol particles, such as atmospheric aerosols where quantitative photokinetic data are critical for climate predictions. Enzymes are capable of directing complex stereospecific transformations and of accelerating reaction rates many orders of magnitude. As even the simplest known enzymes comprise thousands of atoms, the question arises as to how such exquisite catalysts evolved.
A logical predecessor would be shorter peptides, but they lack the defined structure and size that are apparently necessary for enzyme functions. We have hypothesized that amyloids could have been the catalytically active precursor to modern enzymes. To test this hypothesis, we designed an amyloid peptide library that could be screened for catalytic activity. Our approach, amenable to high-throughput methodologies, allowed us to find several peptides and peptide mixtures that form amyloids with esterase activity.
These results indicate that amyloids, with their stability in a wide range of conditions and their potential as catalysts with low sequence specificity, would indeed be fitting precursors to modern enzymes. Furthermore, our approach can be efficiently expanded upon in library size, screening conditions, and target activity to yield novel amyloid catalysts with potential applications in aqueous-organic mixtures, at high temperature and in other extreme conditions that could be advantageous for industrial applications.
All attosecond time-resolved measurements have so far relied on the use of intense near-infrared laser pulses. In particular, attosecond streaking, laser-induced electron diffraction and high-harmonic generation all make use of non-perturbative light—matter interactions. Remarkably, the effect of the strong laser field on the studied sample has often been neglected in previous studies.
Here we use high-harmonic spectroscopy to measure laser-induced modifications of the electronic structure of molecules. We study high-harmonic spectra of spatially oriented CH3F and CH3Br as generic examples of polar polyatomic molecules. We accurately measure intensity ratios of even and odd-harmonic orders, and of the emission from aligned and unaligned molecules.
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We show that these robust observables reveal a substantial modification of the molecular electronic structure by the external laser field. Our insights offer new challenges and opportunities for a range of emerging strong-field attosecond spectroscopies. A multidimensional NMR study characterizing the intermediate accompanied with site-specific fluorescence study suggests that the N-terminal and central portions mainly participate in the helix-rich intermediate formation while the C-terminus remained in an extended conformation.
The review process of academic, scientific research and its basic tenets is considered, thereby distinguishing between i reviewing of manuscripts to be published in the scientific literature, ii reviewing of research proposals to be financed by funding agencies, iii reviewing of educational or research institutions with respect to their proper functioning, and iv reviewing of scientists with the aim of appointing or tenuring faculty.
The flavoenzyme pyranose dehydrogenase PDH from the litter decomposing fungus Agaricus meleagris oxidizes many different carbohydrates occurring during lignin degradation. This promiscuous substrate specificity makes PDH a promising catalyst for bioelectrochemical applications. A generalized approach to simulate all 32 possible aldohexopyranoses in the course of one or a few molecular dynamics MD simulations is reported. The agreement was very good for one of the poses, in which the sugars are positioned in the active site for oxidation at C1 or C2.
Furthermore, several oxidation products were predicted for sugars that have not yet been tested experimentally, directing further analyses. This study rationalizes the relationship between binding free energies and substrate promiscuity in PDH, providing novel insights for its applicability in bioelectrochemistry. The results suggest that a similar approach could be applied to study promiscuity of other enzymes.
The p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily, is required as a co-receptor for the Nogo receptor NgR to mediate the activity of myelin-associated inhibitors such as Nogo, MAG, and OMgp. Here we report that p45 markedly interferes with the function of p75 as a co-receptor for NgR.
P45 forms heterodimers with p75 and thereby blocks RhoA activation and inhibition of neurite outgrowth induced by myelin-associated inhibitors. To understand the underlying mechanisms, we have determined the three-dimensional NMR solution structure of the intracellular domain of p45 and characterized its interaction with p We have identified the residues involved in such interaction by NMR and co-immunoprecipitation. The DD of p45 binds the DD of p75 by electrostatic interactions.
In addition, previous reports suggested that Cys in the p75 TM domain is required for signaling. We found that the interaction of the cysteine 58 of p45 with the cysteine of p75 within the TM domain is necessary for p45—p75 heterodimerization. These results suggest a mechanism involving both the TM domain and the DD of p45 to regulate pmediated signaling. The [Het-s] prion of the fungus Podospora anserina represents a good model system for studying the structure-function relationship in amyloid proteins because a high resolution solid-state NMR structure of the amyloid prion form of the HET-s prion forming domain PFD is available.
A C-terminal loop folds back onto the rigid core region and forms a more dynamic semi-hydrophobic pocket extending the hydrophobic core. Different structural elements identified in the prion fold such as the triangular hydrophobic core, the salt bridges, the asparagines ladders and the C-terminal loop were altered and the effect of these mutations on prion function, fibril structure and stability was assayed. Prion activity and structure were found to be very robust; only a few key mutations were able to corrupt structure and function.
While some mutations strongly destabilize the fold, many substitutions in fact increase stability of the fold. This increase in structural stability did not influence prion formation propensity in vivo. However, if an Ala replacement did alter the structure of the core or did influence the shape of the denaturation curve, the corresponding variant showed a decreased prion efficacy.
It is also the finding that in addition to the structural elements of the rigid core region, the aromatic residues in the C-terminal semi-hydrophobic pocket are critical for prion propagation. Mutations in the latter region either positively or negatively affected prion formation. Although these clusters are generally well-studied cofactors, their significance in the new contexts often remains elusive.
One fascinating example is a tryptophanyl-tRNA synthetase from the thermophilic bacterium Thermotoga maritima, TmTrpRS, that has recently been structurally characterized. It represents an unprecedented connection among a primordial iron—sulfur cofactor, RNA and protein biosynthesis. This motif provides not only affinity but also specificity by creating a structural and energetical penalty for the binding of other bases, such as uracil. We show that both forms, which can each be produced as a pure polymorph, are greatly different in secondary structure. The two forms show a different molecular arrangement in the unit cell and distinct dynamic features, while sharing a highly flexible C-terminal domain.
The use of reproducible, well-identified conditions for sample preparation and the recording of identical NMR experiments allows for a direct comparison of the results. Polymer-clay nanocomposites PCNCs containing either a rubber or an acrylate polymer were prepared by drying or co-precipitating polymer latex and nanolayered clay synthetic and natural suspensions. The interface between the polymer and the clay nanoparticles was studied by electron paramagnetic resonance EPR techniques by selectively addressing spin probes either to the surfactant layer labeled stearic acid or the clay surface labeled catamine.
Analysis of these couplings indicates that the integrity of the surfactant layer is conserved and that there are sizeable ionic regions containing sodium ions directly beyond the surfactant layer. Simulations of the very weak couplings demonstrated that the HYSCORE spectra are sensitive to the composition of the clay and whether or not clay platelets stack. Corticotropin-Releasing Factor Receptors CRFRs are class B1 G-protein-coupled receptors, which bind peptides of the corticotropin releasing factor family and are key mediators in the stress response.
Protein expression parameters were assessed, including the influence of E. In general, the large majority of receptor proteins became inserted in the bacterial membrane. We suggest that our E. Fingerprint similarity is a common method for comparing chemical structures. Similarity is an appealing approach because, with many fingerprint types, it provides intuitive results: a chemist looking at two molecules can understand why they have been determined to be similar.
This transparency is partially lost with the fuzzier similarity methods that are often used for scaffold hopping and tends to vanish completely when molecular fingerprints are used as inputs to machine-learning ML models. Here we present similarity maps, a straightforward and general strategy to visualize the atomic contributions to the similarity between two molecules or the predicted probability of a ML model. An open-source implementation of the method is provided.
Following spinal cord injury, transgenic mice over-expressing p45 exhibit increased neuronal survival, decreased retraction of corticospinal tract fibers and improved functional recovery. Understanding pmediated cellular and molecular mechanisms may provide insights into facilitating nerve regeneration in humans. Similarity-search methods using molecular fingerprints are an important tool for ligand-based virtual screening. A huge variety of fingerprints exist and their performance, usually assessed in retrospective benchmarking studies using data sets with known actives and known or assumed inactives, depends largely on the validation data sets used and the similarity measure used.
Comparing new methods to existing ones in any systematic way is rather difficult due to the lack of standard data sets and evaluation procedures. Here, we present a standard platform for the benchmarking of 2D fingerprints. The open-source platform contains all source code, structural data for the actives and inactives used drawn from three publicly available collections of data sets , and lists of randomly selected query molecules to be used for statistically valid comparisons of methods.
This allows the exact reproduction and comparison of results for future studies. The results for 12 standard fingerprints together with two simple baseline fingerprints assessed by seven evaluation methods are shown together with the correlations between methods. High correlations were found between the 12 fingerprints and a careful statistical analysis showed that only the two baseline fingerprints were different from the others in a statistically significant way.
High correlations were also found between six of the seven evaluation methods, indicating that despite their seeming differences, many of these methods are similar to each other. Respiratory Syncytial Virus RSV is a highly pathogenic member of the Paramyxoviridae that causes severe respiratory tract infections. Reports in the literature have indicated that to infect cells the incoming viruses either fuse their envelope directly with the plasma membrane or exploit clathrin-mediated endocytosis.
To study the entry process in human tissue culture cells HeLa, A , we used fluorescence microscopy and developed quantitative, FACS-based assays to follow virus binding to cells, endocytosis, intracellular trafficking, membrane fusion, and infection. A variety of perturbants were employed to characterize the cellular processes involved. This led to a series of dramatic actin rearrangements; the cells rounded up, plasma membrane blebs were formed, and there was a significant increase in fluid uptake.
The RSV was rapidly and efficiently internalized by an actin-dependent process that had all hallmarks of macropinocytosis. Rather than fusing with the plasma membrane, the viruses thus entered Rab5-positive, fluid-filled macropinosomes, and fused with the membranes of these on the average 50 min after internalization. Rab5 was required for infection. To find an explanation for the endocytosis requirement, which is unusual among paramyxoviruses, we analyzed the fusion protein, F, and could show that, although already cleaved by a furin family protease once, it underwent a second, critical proteolytic cleavage after internalization.
This cleavage by a furin-like protease removed a small peptide from the F1 subunits, and made the virus infectious. Because membrane proteins need to be extracted from their natural environment and reconstituted in artificial milieus for the 3D structure determination by X-ray crystallography or NMR, the search for membrane mimetic that conserve the native structure and functional activities remains challenging. The analysis of 2D [15N,1H]-TROSY spectra shows that only a careful usage of low amounts of mixed detergents did not perturb the cytoplasmic domain while solubilizing in parallel the transmembrane segments with good spectral quality.
In contrast, the incorporation of YgaP into nanodiscs appeared to be straightforward and yielded a surprisingly high quality [15N,1H]-TROSY spectrum opening an avenue for the structural studies of a helical membrane protein in a bilayer system by solution state NMR. The contemporary proteinogenic repertoire contains 20 amino acids with diverse functional groups and side chain geometries.
Primordial proteins, in contrast, were presumably constructed from a subset of these building blocks. Subsequent expansion of the proteinogenic alphabet would have enhanced their capabilities, fostering the metabolic prowess and organismal fitness of early living systems. While the addition of amino acids bearing innovative functional groups directly enhances the chemical repertoire of proteomes, the inclusion of chemically redundant monomers is difficult to rationalize.
Here, we studied how a simplified chorismate mutase evolves upon expanding its amino acid alphabet from nine to potentially 20 letters. The increase in fitness they confer indicates that building blocks with very similar side chain structures are highly beneficial for fine-tuning protein structure and function. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway.
Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Homepage Navigation Content Sitemap Search. The Department. Doctoral Studies. Continuing Education. Chemical Research in Toxicology , vol. DOI: Clarke, Harry L. Anderson, Christiane R.
Timmel and Gunnar Jeschke. Physical Chemistry Chemical Physics , vol. Journal of Chemical Theory and Computation , vol. Frontiers in Chemistry , vol. Gabriele Stevanato, Dominik J. Journal of the American Chemical Society , vol. Juan A. Gerez, Natalia C. Prymaczok, Edward Rockenstein, Uli S.
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Bratholm, Simon J. Bennie, Alain C. Vaucher, Markus Reiher and David R. Journal of Physical Chemistry A , vol. Julien Orts, Marielle A. Saupe and Roland Riek. ChemBioChem , vol. Helvetica Chimica Acta , vol. Oleg N. Ulenikov, Elena S. Bekhtereva, Olga V. Gromova, Anastatsia G. Ziatkova, Martin Quack, Georg C. Mellau, Christian Sydow and Sigurd Bauerecker.
Journal of Quantitative Spectroscopy and Radiative Transfer , vol. The Journal of Physical Chemistry B , vol. Aaron C. Physical Review Letters , vol. The Journal of Physical Chemistry Letters , vol. Ion-mediated hydrogen-bond rearrangement through tunnelling in the iodide—dihydrate complex. Nature Chemistry , vol. Backbone and side-chain chemical shift assignments of full-length, apo, human Pin1, a phosphoprotein regulator with interdomain allostery.
Alexandra Born, Parker J. Nichols, Morkos A. Henen, Celestine N. Biomolecular NMR Assignments , vol. Toward the elucidation of the mechanism for passive membrane permeability of cyclic peptides. Future Medicinal Chemistry , vol. Chimia , vol. Ferreiro, Egor Chasovskikh and Ruth Signorell. The Journal of Physical Chemistry A , vol. The Journal of Organic Chemistry , vol. Salumbides, Kjeld S. Nonadiabatic quantum transition-state theory in the golden-rule limit.
Theory and application to model systems. The Journal of Chemical Physics , vol. Yan M. Goncalves, Caroline Senac, Patrick F. Fuchs, Philippe H. Optimization of highly excited matrix product states with an application to vibrational spectroscopy. Denis V. Sosnovsky, Nikita N. Alexander A.
Meier and Thomas Wiegand. ChemPhysChem , vol. General regularization framework for DEER spectroscopy. Wilkins, Benjamin A. Manolopoulos, Thomas E. Markland, Jeremy O. Richardson, Alexandre Tkatchenko, Gareth A. Computer Physics Communications , vol. Truhlar and Laura Gagliardi. Chemical Science , vol. Protein sample preparation for solid-state NMR investigations. Progress in Nuclear Magnetic Resonance Spectroscopy , vol. Journal of Biomolecular NMR , vol. Microscale 3D imaging by magnetic resonance force microscopy using full-volume Fourier- and Hadamard-encoding.
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Cell , vol. Simon L. Angewandte Chemie. International Edition , vol. Nature Communications , vol. From metastable to coherent sets - Time-discretization schemes. Chaos , vol. International Journal of Mass Spectrometry , vol. Detection of liquids by magnetic resonance force microscopy in the gradient-on-cantilever geometry.
Comparison of the functional properties of trimeric and monomeric CaiT of Escherichia coli. Scientific Reports , vol. Assessing relative humidity dependent photoacoustics to retrieve mass accommodation coefficients of single optically trapped aerosol particles. Matus E. Diveky, Sandra Roy, Johannes W. Prota, Michel O. Steinmetz and John H. Mukul G. Jain, Kaustubh R.
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Mote, Johannes Hellwagner, G. Rajalakshmi, Matthias Ernst, P. Madhu and Vipin Agarwal. Cold Spring Harbor Perspectives in Biology , pp. On the identity of the identity operator in nonadiabatic linearized semiclassical dynamics. Fluorescence-lifetime-limited trapping of Rydberg helium atoms on a chip. Ferreiro, Kyoko K. Tanaka and Ruth Signorell. Journal of Chemical Physics , vol. Biophysical Journal , vol. Semiempirical molecular orbital models based on the neglect of diatomic differential overlap approximation.
International journal of quantum chemistry , vol. Ab initio instanton rate theory made efficient using Gaussian process regression. Faraday Discussions , vol. Molecular-beam resonance method with Zeeman-decelerated samples: Application to metastable helium molecules. Physical Review A , vol. Lipid- and cholesterol-mediated timescale-specific modulation of the outer membrane protein X dynamics in lipid bilayers.
Explicitly correlated Gaussian functions with shifted-center and projection techniques in pre-Born-Oppenheimer calculations. Quantum system partitioning at the single-particle level. Arturi, Jeroen A. ChemistrySelect , vol. Starsich, Matthias Ernst and Sebastian Kozerke. Journal of Physical Chemistry C , vol. Density artefacts at interfaces caused by multiple time-step effects in molecular dynamics simulations. F Research , vol. Applied magnetic resonance , vol.
Stephan Pribitzer, Luis F. Applied Magnetic Resonance , vol. Time in quantum mechanics: A fresh look at the continuity equation. Using a passively stable attosecond beamline for relative photoemission time delays at high XUV photon energies. Optics Express , vol. Relativistic quantum chemical calculations show that the uranium molecule U2 has a quadruple bond. Chaudhari, Dominik J. Kubicki, Aaron J. Rossini, Ilia B. Benson J. Jelier, Pascal F. Journal of Molecular Biology , vol. Observing broken inversion symmetry in solids using two-color high-order harmonic spectroscopy.
Chemistry - A European Journal , vol. Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins. Science Advances , vol. Direct amide N to C transfers for solid-state assignment experiments in deuterated proteins. Nuclear magnetic resonance structure-based drug design. Extreme-ultraviolet high-order harmonic generation from few-cycle annular beams. Optics Letters , vol. Photoionization delays in xenon using single-shot referencing in the collinear back-focusing geometry.
Extreme-ultraviolet high-harmonic generation in liquids. Physical Review X , vol. Morphology and motion of single optically trapped aerosol particles from digital holography. Transition from Academia to Industry and Back. Parker J. Nichols, Alexandra Born, Morkos A. Henen, Dean Strotz, Celestine N. Chi, Peter Guntert and Beat Vogeli. Conical-intersection dynamics and ground-state chemistry probed by extreme-ultraviolet time-resolved photoelectron spectroscopy.
Proteome-wide analysis of phospho-regulated PDZ domain interactions. Gustav N. Chi and Ylva Ivarsson. Molecular Systems Biology , vol. Group, Capture and characterization of a reactive haem—carbenoid complex in an artificial metalloenzyme. Nature Catalysis , vol. Setting the magic angle for fast magic-angle spinning probes.
A molecular mechanism for the enzymatic methylation of nitrogen atoms within peptide bonds. Haigang Song, Niels S. Allain and Beat H. Ab initio calculation of femtosecond-time-resolved photoelectron spectra of NO2 after excitation to the A-band. Attosecond coherent control of oxygen dissociation by XUV-IR laser fields using three-dimensional momentum imaging. Predrag Ranitovic, Flavius Sturm, X. Tong, T. Wright, D. Ray, I. Zalyubovskya, N.
Shivaram, A. Belkacem, D. Slaughter and T. Dissociation Energy of the Hydrogen Molecule at Accuracy. Bethlem, Kjeld S. Eikema, Edcel J. Tao, Shui M. Hu and Christian Jungen. Selective labeling and unlabeling strategies in protein solid-state NMR spectroscopy. Anisotropic reaction field correction for long-range electrostatic interactions in molecular dynamics simulations. High-resolution small RNA structures from exact nuclear Overhauser enhancement measurements without additional restraints.
Communications Biology , vol. A, Bern: Swiss Chemical Society, Research Collection. Communication: Heavy-Rydberg states of HD and the electron affinity of the deuterium atom. Irina B. Bolotova, Oleg N. Journal of Molecular Spectroscopy , vol. Electron scattering in large water clusters from photoelectron imaging with high harmonic radiation.
Thomas E. Yoder and Ruth Signorell. Leigh Martin, Roger Y. Bello, Craig W. Nonlocal mechanisms of attosecond interferometry and implications for condensed-phase experiments. Magnetochemistry , vol. Special Issue, pp. Complete reconstruction of ultra-broadband isolated attosecond pulses including partial averaging over the angular distribution. Femtosecond X-ray coherent diffraction of aligned amyloid fibrils on low background graphene.
Wojtas, Matthew A. Ginn, Rick P. Phase transition dynamics of single optically trapped aqueous potassium carbonate particles. Thomas Duhamel, Christopher J. ACS Catalysis , vol. Angewandte Chemie - International Edition , vol. Angewandte Chemie , vol. Statistical Analysis of Semiclassical Dispersion Corrections. Photoelectron spectrometer for liquid and gas-phase attosecond spectroscopy with field-free and magnetic bottle operation modes. Review of Scientific Instruments , vol.
Gromova, Martin Quack, Georg C. High-order harmonic source spanning up to the oxygen K-edge based on filamentation pulse compression. Quantitative mass imaging of single biological macromolecules. Marklund, Miranda P. Collier, Shane A. Galpin, Weston B. Struwe, Justin L.
Benesch and Philipp Kukura. Science , vol. Andrey A. Kuzhelev, Olesya A. Krumkacheva, Georgiy Y. Shevelev, Maxim Yulikov, Matvey V. Fedin and Elena G. Tran T. Structure determination of protein-ligand complexes by NMR in solution. Methods , vol. Quantitative analysis of zero-field splitting parameter distributions in Gd III complexes.
Jessica A. Sherwin and Maxim Yulikov. Double resonance calibration of g factor standards: Carbon fibers as a high precision standard. Effects of tunnelling and asymmetry for system-bath models of electron transfer. Correction to: Characterization of fibril dynamics on three timescales by solid-state NMR. Albert A. Meier and Matthias Ernst. Generalized elimination of the global translation from explicitly correlated Gaussian functions. Extracting attosecond delays from spectrally overlapping interferograms. Journal of Optics B , vol. The contribution of modern EPR to structural biology.
Emerging Topics in Life Sciences , pp. ACS Central Science , vol. Wittmann, Beat H. Kong O. Solid State Nuclear Magnetic Resonance , vol. Wilfred F. Dynamical decoupling of nitroxides in o-terphenyl: a study of temperature, deuteration and concentration effects. Structure and dynamics of the radical cation of ethane arising from the Jahn-Teller and Pseudo-Jahn-Teller effects.
Ugo Jacovella, Christopher J. Roadmap of ultrafast x-ray atomic and molecular physics. MMM: A toolbox for integrative structure modeling. Protein Science , vol. Direct hyperpolarization of micro- and nanodiamonds for bioimaging applications — Considerations on particle size, functionalization and polarization loss. Optimized "detectors" for dynamics analysis in solid-state NMR. Bekhtereva, Irina B. Bolotova, H. Hollenstein, Martin Quack and Oleg N. Molecular Physics , vol. High power hollow-core fiber compression of Yb lasers as ideal drivers for HHG. Digital holography of optically-trapped aerosol particles.
Communications Chemistry , vol. Measurement of the Berry curvature of solids using high-harmonic spectroscopy. Nachrichten aus der Chemie , vol. International Reviews in Physical Chemistry , vol. Research strategies in computational chemistry. Infozine , vol. S2, pp.