Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography
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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
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Determination of Thiol Protonation States by Sulfur X-ray Spectroscopy in Biological Systems
Cysteine is one of the most functionally diverse of the proteinogenic amino acids, owing to its reactive thiol side chain that can undergo deprotonation to form a strongly nucleophilic thiolate. However, few techniques can directly interrogate sulfur charge and covalency in cysteine, particularly in proteins. X-ray spectroscopies provide an element specific probe of sulfur. We demonstrate the sensitivity of S Kβ and Kα X-ray emission spectroscopy (XES) to cysteine ionization and compare it to S K-edge X-ray absorption spectroscopy (XAS) in the physiologically relevant biomolecules l-cysteine and N-acetyl-l-cysteine at room temperature in solution phase. Kβ XES and K-edge XAS are most sensitive to chemical changes at the cysteine thiol and can be used to evaluate the composition of thiol/thiolate mixtures. Furthermore, these results provide a foundation for assessing the pK a of functionally significant cysteine residues in proteins and open the door to time-resolved studies of cysteine-dependent enzymes.
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Design of Large Stokes Shift Fluorescent Proteins Based on Excited State Proton Transfer of an Engin
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Santos, Elizabeth M.↗
Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease
The main protease (M pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics.
59 BASIC BIOLOGICAL SCIENCES↗
Screening of transition metals for PFAS adsorption: A comparative DFT investigation
Transition metals are promising candidates for catalytic destruction of per- and polyfluoroalkyl substances (PFAS). This study employed density functional theory (DFT) calculations to systematically investigate the adsorption of PFAS, which is a critical step in the catalytic process, onto a group of transition metals, namely Cu, Pd, Pt, and Rh. The investigation considered the influence of different PFAS characteristics, including chain length, functional group (i.e., sulfonic vs. carboxylic), and protonation state (i.e., protonated, anionic, and deprotonated radical) on the adsorption mechanism. Overall, the findings indicated that the adsorption of PFAS on transition metals exhibited thermodynamically favorable energetics, with Rh showing the most favorable adsorption for PFAS. However, the adsorption strength was significantly dependent on the protonation state of PFAS. Cu was the highest electron donor, while Pt was the highest electron acceptor. Results were compared to experimental studies in the literature for qualitative validation.
Adsorption↗
Spectral Signatures of Ultrafast Excited-State Intramolecular Proton Transfer from Computational Multi-edge Transient X-ray Absorption Spectroscopy
Excited state intramolecular proton transfer (ESIPT) is a fundamental chemical process with several applications. Ultrafast ESIPT involves coupled electronic and atomic motions and has been primarily studied using femtosecond optical spectroscopy. X-ray spectroscopy is particularly useful because it is element-specic and enables direct, individual probes of the proton donating and accepting atoms. Here, we report a computational study to resolve the ESIPT in 10-Hydroxybenzo[h]quinoline (HBQ), an intramolecularly hydrogen bonded compound, using time-dependent density functional theory combined with ab initio molecular dynamics (AIMD) and time-resolved X-ray absorption spectroscopy (XAS) computations to track the ultrafast excited-state dynamics. Overall, our results reveal clear X-ray spectral signatures of coupled electronic and atomic motions during and following ESIPT at the oxygen and nitrogen K-edge paving the way for future experiments at X-ray free electron lasers.
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Capturing Coupled Structural and Electronic Motions During Excited-State Intramolecular Proton Transfer via Computational Multiedge Resonant Inelastic X-ray Scattering
Proton-transfer processes build the foundation of many chemical processes. In Excited State Intramolecular Proton Transfer (ESIPT) processes the proton transfer process is impulsively started through light. Here, in this study, we explore the changes in coupled atomic and electronic motions during and following ESIPT through computational time-resolved Resonant Inelastic X-ray Scattering (trRIXS). Excited-state Ab Initio Molecular Dynamics (AIMD) simulations combined with Time-Dependent Density Functional Theory (TDDFT) calculations were performed for 10-hydroxybenzo[h]quinoline to obtain trRIXS signatures. RIXS at both the nitrogen and oxygen K-edges were computed to resolve the dynamics electronic structure from both the proton donor and acceptor perspective. The results show how RIXS can reveal the local electronic structure, the coupling between different electronic states and how electronic structure and coupling change during the proton transfer process. Additionally, we observe a strong correlation between spectral changes and structural changes during ESIPT.
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The N3/TiO 2 interfacial structure is dependent on the pH conditions during sensitization
The electronic structure of the N3/TiO 2 interface can directly influence the performance of a dye sensitized solar cell (DSSC). Therefore, it is crucial to understand the parameters that control the dye’s orientation on the semiconductor’s surface. A typical step in DSSC fabrication is to submerge the nanoparticulate semiconductor film in a solution containing the dye, the sensitizing solution. The pH of the N3 sensitizing solution determines the distribution of the N3 protonation states that exist in solution. Altering the pH of the sensitizing solution changes the N3 protonation states that exist in solution and, subsequently, the N3 protonation states that anchor to the TiO 2 substrate. We utilize the surface specific technique of heterodyne detected vibrational sum frequency generation spectroscopy to determine the binding geometry of N3 on a TiO 2 surface as a function of the sensitizing solution pH conditions. It is determined that significant reorientation of the dye occurs in pH ≤ 2.0 conditions due to the lack of N3-dye carboxylate anchoring groups participating in adsorption to the TiO 2 substrate. Consequently, the change in molecular geometry is met with a change in the interfacial electronic structure that can hinder electron transfer in DSSC architectures.
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Unusual zwitterionic catalytic site of SARS–CoV-2 main protease revealed by neutron crystallography
The main protease (3CL M pro ) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL M pro possesses an unusual catalytic dyad composed of Cys 145 and His 41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL M pro , which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys 145 is in the negatively charged thiolate state and His 41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.
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Steric effects in light-induced solvent proton abstraction
The significance of solvent structural factors in the excited-state proton transfer (ESPT) reactions of Schiff bases with alcohols is reported here. In this work, we use the super photobase FR0-SB and a series of primary, secondary, and tertiary alcohol solvents to illustrate the steric issues associated with solvent to photobase proton transfer. Steady-state and time-resolved fluorescence data show that ESPT occurs readily for primary alcohols, with a probability proportional to the relative –OH concentration. For secondary alcohols, ESPT is greatly diminished, consistent with the barrier heights obtained using quantum chemistry calculations. ESPT is not observed in the tertiary alcohol. We explain ESPT using a model involving an intermediate hydrogen-bonded complex where the proton is “shared” by the Schiff base and the alcohol. The formation of this complex depends on the ability of the alcohol solvent to achieve spatial proximity to and alignment with the FR0-SB* imine lone pair stabilized by the solvent environment.
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Excited State Intramolecular Proton Transfer with Nuclear-Electronic Orbital Ehrenfest Dynamics
The recent development of the Ehrenfest dynamics approach in the nuclear-electronic orbital (NEO) framework provides a promising way to simulate coupled nuclear-electronic dynamics. Our previous study showed that the NEO-Ehrenfest approach with a semi- classical traveling proton basis method yields accurate predictions of molecular vibrational frequencies. In this work, we provide a more thorough analysis of the semiclassical traveling proton basis method to elucidate its validity and convergence behavior. We also conduct NEO-Ehrenfest dynamics simulations to study an excited state intramolecular proton transfer process. These simulations reveal that nuclear quantum effects influence the predictions of proton transfer reaction rates and kinetic isotope effects due to the intrinsic delocalized nature of the quantum nuclear wave function. This work illustrates the importance of nuclear quantum effects in coupled nuclear-electronic dynamical processes and shows that the NEO-Ehrenfest approach can be a powerful tool to provide insights and predictions for these processes.
Zhao, Luning↗
Measurement of $\nu_\mu$ CC Interactions With Two-Proton Final State in MINERvA
This dissertation presents a measurement of charged–current (CC) muon–neutrino interactions with exactly two protons and no pions in the final state (CC~$2p\,0\pi$), using data collected by the MINERvA detector in the NuMI medium–energy beam at Fermilab. Such two–proton topologies are a sensitive probe of nuclear dynamics in the few–GeV regime, including multi–nucleon correlations (npnh, notably $2p2h$) and intranuclear final–state interactions (FSI) such as pion absorption and nucleon rescattering. A precise experimental characterization of these processes is essential both for neutrino–interaction theory and for reducing systematic uncertainties in oscillation experiments that rely on accurate modeling of neutrino–nucleus interactions. Events are selected by requiring a $\nu_\mu$ CC interaction with a reconstructed $\mu^-$ and two proton tracks originating from a common vertex in MINERvA’s finely segmented scintillator tracker, with no reconstructed mesons. Muon charge and momentum are constrained by matching to the MINOS Near Detector, while proton identification exploits energy–loss profiles and stopping–proton features. Backgrounds from pion–producing channels that enter the signal region through FSI or reconstruction effects are constrained with data–driven sidebands (Michel–electron and isolated–cluster “blob” samples) and tuned via a simultaneous fit across signal and sideband regions. To correct detector resolution and acceptance effects, the analysis employs iterative Bayesian unfolding with extensive validation: statistical pseudo–experiments, and robustness checks against generator systematic “universes” and additional strong shape warps. Single–differential cross sections are reported for three observables tailored to the two–proton final state: the opening–angle cosine $\cos\!\left(\theta_{pp}\right)$, the leading–proton momentum, and the subleading–proton momentum. Systematic uncertainties include contributions from neutrino flux, interaction modeling (e.g., npnh and resonance parameters, pion FSI), and detector response (calibration, reconstruction efficiencies). The resulting distributions provide targeted constraints on the interplay of multi–nucleon dynamics and FSI that shape CC~$2p\,0\pi$ final states on hydrocarbon. Comparisons to modern GENIE–based simulations highlight kinematic regions where model components require refinement. These measurements thus inform generator tuning and improve the reliability of neutrino–energy reconstruction strategies for current and future long–baseline oscillation programs.
Syrotenko, Vladyslav S. [Tufts U.]↗
Universality of critical active site glutamate as an acid–base catalyst in serine hydroxymethyltransferase function
Neutron crystallography revealed protonation states in Tth SHMT-FA complex. Glu53 is protonated but other residues maintain protonation states upon FA binding. Structural analyses support key roles of Glu53 and gating loop dynamics in SHMT function.
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First measurement of differential cross sections for muon neutrino charged current interactions on argon with a two-proton final state using the MicroBooNE detector
We present the first measurement of differential cross sections for charged-current muon neutrino interactions on argon with one muon, two protons, and no pions in the final state. These final states are dominated by two-nucleon knockout interactions, which are complicated to model and for which there is currently limited information about the characteristics of these interactions in existing neutrino-nucleus scattering data. Detailed investigations of two-nucleon knockout are vital to support upcoming experiments exploring the nature of the neutrino. Among the different kinematic quantities measured, the opening angle between the two protons, the angle between the total proton momentum and the muon, and the total transverse momentum of the final state system are most sensitive to the underlying physics processes as embodied in various theoretical models.
2-particle 2-hole states↗
Room-temperature neutron and X-ray data collection of 3CL M pro from SARS-CoV-2
The replication of SARS-CoV-2 produces two large polyproteins, pp1a and pp1ab, that are inactive until cleavage by the viral chymotrypsin-like cysteine protease enzyme (3CL M pro ) into a series of smaller functional proteins. At the heart of 3CL M pro is an unusual catalytic dyad formed by the side chains of His41 and Cys145 and a coordinated water molecule. The catalytic mechanism by which the enzyme operates is still unknown, as crucial information on the protonation states within the active site is unclear. To experimentally determine the protonation states of the catalytic site and of the other residues in the substrate-binding cavity, and to visualize the hydrogen-bonding networks throughout the enzyme, room-temperature neutron and X-ray data were collected from a large H/D-exchanged crystal of ligand-free (apo) 3CL M pro .
3CL Mpro↗
Search for resonant $WZ$ production in the fully leptonic final state in proton–proton collisions at $\sqrt{s}$= 13 TeV with the ATLAS detector
A search for a $WZ$ resonance, in the fully leptonic final state (electrons or muons), is performed using 139 fb –1 of data collected at a centre-of-mass energy of 13 TeV by the ATLAS detector at the Large Hadron Collider. The results are interpreted in terms of a singly charged Higgs boson of the Georgi–Machacek model, produced by WZ fusion, and of a Heavy Vector Triplet, with the resonance produced by $WZ$ fusion or the Drell–Yan process. No significant excess over the Standard Model prediction is observed and limits are set on the production cross-section times branching ratio as a function of the resonance mass for these processes.
72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
Search for low-mass dilepton resonances in Higgs boson decays to four-lepton final states in proton–proton collisions at $\sqrt{s}=13\,\text {TeV} $
A search for low-mass dilepton resonances in Higgs boson decays is conducted in the four-lepton final state. The decay is assumed to proceed via a pair of beyond the standard model particles, or one such particle and a ${\mathrm{Z}}$ boson. The search uses proton–proton collision data collected with the CMS detector at the CERN LHC, corresponding to an integrated luminosity of 137$\,\text {fb}^{-1}$, at a center-of-mass energy $\sqrt{s} = 13\,\text {TeV} $. No significant deviation from the standard model expectation is observed. Upper limits at 95% confidence level are set on model-independent Higgs boson decay branching fractions. Additionally, limits on dark photon and axion-like particle production, based on two specific models, are reported.
72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗