Ultrafast control of the LnF+/LnO+ ratio from Ln(hfac)3.

The photo-induced dissociative ionization of lanthanide complexes Ln(hfac)3 (Ln = Pr, Er, Yb) is studied using ultrafast shaped laser pulses in a time-of-flight (TOF) mass spectrometry setup. Various fluorine and Ln-containing mass fragments were observed, which can be interpreted by the photo-fragmentation mechanistic pathway involving C-C bond rotation processes proposed previously. A set of experiments used pulse shaping guided by closed-loop feedback control to identify pulses that optimize the ratio of LnF+/LnO+. In agreement with previous studies in which very little LnO+ was observed, broad pulses were found to maximize the LnF+/LnO+ ratio, which involves metal-ligand bond-breaking followed by bond rotation and bond rearrangement. In contrast, a transform limited (TL) pulse favored the formation of LnO+. Finally, the recently developed experimental control pulse slicing (CPS) technique was applied to elucidate the dynamics induced by fields that either maximize or minimize the LnF+/LnO+ ratio, which also indicates that longer laser pulses facilitate LnF+ formation during the C-C bond rotation dissociative-ionization process.

The Early Era of Laser-Selective Chemistry 1960∼1985: Roots of Modern Quantum Control.

Physicists revolutionized the scientific world when they invented the laser in 1960. During the next two decades, fruitful interplay occurred between theoreticians and experimentalists seeking progress in laser-selective chemistry. In the Early Era, defined as 1960∼1985, scientists gradually realized the immense complexity of the problem of performing tailored manipulations at the molecular scale. However, their efforts opened the doors to a new, broader scientific field of research called quantum control which developed in the Modern Era, defined as 1985 to the present time. This Perspective aims to show that the roots of quantum control may be linked to endeavors to manipulate chemical reactions with lasers and thus reaches as far back as the invention of the laser in 1960. We will emphasize the role of advancing technology, the prescience in the questions raised by researchers, and the role of interdisciplinary research. The Perspective concludes with an assessment of what was achieved in the Early Era.

The Surprising Ease of Finding Optimal Solutions for Controlling Nonlinear Phenomena in Quantum and Classical Complex Systems.

This Perspective addresses the often observed surprising ease of achieving optimal control of nonlinear phenomena in quantum and classical complex systems. The circumstances involved are wide-ranging, with scenarios including manipulation of atomic scale processes, maximization of chemical and material properties or synthesis yields, Nature's optimization of species' populations by natural selection, and directed evolution. Natural evolution will mainly be discussed in terms of laboratory experiments with microorganisms, and the field is also distinct from the other domains where a scientist specifies the goal(s) and oversees the control process. We use the word "control" in reference to all of the available variables, regardless of the circumstance. The empirical observations on the ease of achieving at least good, if not excellent, control in diverse domains of science raise the question of why this occurs despite the generally inherent complexity of the systems in each scenario. The key to addressing the question lies in examining the associated control landscape, which is defined as the optimization objective as a function of the control variables that can be as diverse as the phenomena under consideration. Controls may range from laser pulses, chemical reagents, chemical processing conditions, out to nucleic acids in the genome and more. This Perspective presents a conjecture, based on present findings, that the systematics of readily finding good outcomes from controlled phenomena may be unified through consideration of control landscapes with the same common set of three underlying assumptions─the existence of an optimal solution, the ability for local movement on the landscape, and the availability of sufficient control resources─whose validity needs assessment in each scenario. In practice, many cases permit using myopic gradient-like algorithms while other circumstances utilize algorithms having some elements of stochasticity or introduced noise, depending on whether the landscape is locally smooth or rough. The overarching observation is that only relatively short searches are required despite the common high dimensionality of the available controls in typical scenarios.

Deprotonation of phenol linked to a silicon dioxide surface using adaptive feedback laser control with a heterodyne detected sum frequency generation signal.

The development of laser-controlled surface reactions has been limited by the lack of decisive methods for detecting evolving changes in surface chemistry. In this work, we demonstrate successful laser control of a surface reaction by combining the adaptive feedback control (AFC) technique with surface sensitive spectroscopy to determine the optimally shaped laser pulse. Specifically, we demonstrate laser induced deprotonation of the hydroxyl group of phenol bound to a silicon dioxide substrate. The experiment utilized AFC with heterodyne detected vibrational sum frequency generation (HD-VSFG) as the surface sensitive feedback signal. The versatile combination of AFC with HD-VSFG provides a route to potentially control a wide range of surface reactions.

Interdiction in the Early Folding of the p53 DNA-Binding Domain Leads to Its Amyloid-Like Misfolding.

In this article, we investigate two issues: (a) the initial contact formation events along the folding pathway of the DNA-binding domain of the tumor suppressor protein p53 (core p53); and (b) the intermolecular events leading to its conversion into a prion-like form upon incubation with peptide P8(250-257). In the case of (a), the calculations employ the sequential collapse model (SCM) to identify the segments involved in the initial contact formation events that nucleate the folding pathway. The model predicts that there are several possible initial non-local contacts of comparative stability. The most stable of these possible initial contacts involve the protein segments 159AMAIY163 and 251ILTII255, and it is the only native-like contact. Thus, it is predicted to constitute "Nature's shortcut" to the native structure of the core domain of p53. In the case of issue (b), these findings are then combined with experimental evidence showing that the incubation of the core domain of p53 with peptide P8(250-257), which is equivalent to the native protein segment 250PILTIITL257, leads to an amyloid conformational transition. It is explained how the SCM predicts that P8(250-257) effectively interdicts in the formation of the most stable possible initial contact and, thereby, disrupts the subsequent normal folding. Interdiction by polymeric P8(250-257) seeds is also studied. It is then hypothesized that enhanced folding through one or several of the less stable contacts could play a role in P8(250-257)-promoted core p53 amyloid misfolding. These findings are compared to previous results obtained for the prion protein. Experiments are proposed to test the hypothesis presented regarding core p53 amyloid misfolding.

Selective photo-excitation of molecules enabled by stimulated Raman pre-excitation.

Double resonance excitation, where the energies of vibrational and electronic molecular transitions are combined in a single, sequential excitation process, was introduced in the 1970s but has only been recently applied to microscopy due to the immense progress in Raman spectroscopy. The value of the technique is in combining the chemical selectivity of IR or Raman excitation with the much larger cross-sections of electronic transitions. Recently, it has been shown to be particularly suited for the detection and identification of chromophores at low concentrations and in the presence of spectral crosstalk. However, despite its low quantum yield per pulse sequence, we believe the technique has potential for selective photochemical transformations. There are some cases (e.g., the selective excitation of optogenetic switches) where the low yield may be overcome by repeated excitations to build up biochemically relevant concentrations. Here we show that double resonance excitation using general, non-resonant Raman pre-excitation is a viable candidate for selectively promoting molecules to chemically active energy levels. The use of non-resonant Raman pre-excitation is less constraining than resonant Raman (used in previous double resonance microscopy works) since the choice of Raman pump-Stokes frequencies may be rather freely chosen.

Protein Folding Interdiction Strategy for Therapeutic Drug Development in Viral Diseases: Ebola VP40 and Influenza A M1.

In a recent paper, we proposed the folding interdiction target region (FITR) strategy for therapeutic drug design in SARS-CoV-2. This paper expands the application of the FITR strategy by proposing therapeutic drug design approaches against Ebola virus disease and influenza A. We predict target regions for folding interdicting drugs on correspondingly relevant structural proteins of both pathogenic viruses: VP40 of Ebola, and matrix protein M1 of influenza A. Identification of the protein targets employs the sequential collapse model (SCM) for protein folding. It is explained that the model predicts natural peptide candidates in each case from which to start the search for therapeutic drugs. The paper also discusses how these predictions could be tested, as well as some challenges likely to be found when designing effective therapeutic drugs from the proposed peptide candidates. The FITR strategy opens a potential new avenue for the design of therapeutic drugs that promises to be effective against infectious diseases.

Global Sensitivity Analysis with Mixtures: A Generalized Functional ANOVA Approach.

This work investigates aspects of the global sensitivity analysis of computer codes when alternative plausible distributions for the model inputs are available to the analyst. Analysts may decide to explore results under each distribution or to aggregate the distributions, assigning, for instance, a mixture. In the first case, we lose uniqueness of the sensitivity measures, and in the second case, we lose independence even if the model inputs are independent under each of the assigned distributions. Removing the unique distribution assumption impacts the mathematical properties at the basis of variance-based sensitivity analysis and has consequences on result interpretation as well. We analyze in detail the technical aspects. From this investigation, we derive corresponding recommendations for the risk analyst. We show that an approach based on the generalized functional ANOVA expansion remains theoretically grounded in the presence of a mixture distribution. Numerically, we base the construction of the generalized function ANOVA effects on the diffeomorphic modulation under observable response preserving homotopy regression. Our application addresses the calculation of variance-based sensitivity measures for the well-known Nordhaus' DICE model, when its inputs are assigned a mixture distribution. A discussion of implications for the risk analyst and future research perspectives closes the work.

Identification of Two Early Folding Stage Prion Non-Local Contacts Suggested to Serve as Key Steps in Directing the Final Fold to Be Either Native or Pathogenic.

The initial steps of the folding pathway of the C-terminal domain of the murine prion protein mPrP(90-231) are predicted based on the sequential collapse model (SCM). A non-local dominant contact is found to form between the connecting region between helix 1 and ß-sheet 1 and the C-terminal region of helix 3. This non-local contact nucleates the most populated molten globule-like intermediate along the folding pathway. A less stable early non-local contact between segments 120-124 and 179-183, located in the middle of helix 2, promotes the formation of a less populated molten globule-like intermediate. The formation of the dominant non-local contact constitutes an example of the postulated Nature's Shortcut to the prion protein collapse into the native structure. The possible role of the less populated molten globule-like intermediate is explored as the potential initiation point for the folding for three pathogenic mutants (T182A, I214V, and Q211P in mouse prion numbering) of the prion protein.

Interdiction of Protein Folding for Therapeutic Drug Development in SARS CoV-2.

In this article, we predict the folding initiation events of the ribose phosphatase domain of protein Nsp3 and the receptor binding domain of the spike protein from the severe acute respiratory syndrome (SARS) coronavirus-2. The calculations employ the sequential collapse model and the crystal structures to identify the segments involved in the initial contact formation events of both viral proteins. The initial contact locations may provide good targets for therapeutic drug development. The proposed strategy is based on a drug binding to the contact location, thereby aiming to prevent protein folding. Peptides are suggested as a natural choice for such protein folding interdiction drugs.

Ultrafast Photofragmentation of Ln(hfac)3 with a Proposed Mechanism for forming High Mass Fluorinated Products.

The photo-induced dissociative-ionization of lanthanide complexes Ln(hfac)3 (Ln = Pr, Er, Yb) is studied using intense ultrafast transform limited (TL) and linearly chirped laser pulses in a time-of-flight (TOF) mass spectrometry setup. Various fluorine and Ln-containing high-mass fragments were observed in this experiment, including the molecular parent ion, which have not been seen with previous studies relying on relatively long-duration laser pulses (i.e., ns or longer). These new high-mass observations provide important formerly missing information for deducing a set of photo-fragmentation mechanistic pathways for Ln(hfac)3. An overall ultrafast control mechanism is proposed by combining insights from earlier studies and the fragments observed in this research to result in three main distinct photo-fragmentation processes: (a) ligand-metal charge transfer, (b) CF3 elimination, and (c) C-C bond rotation processes. We conclude that ultrafast dissociative-ionization could be a promising technique for generating high-mass fragments for potential use in material science applications.

Learning-Based Quantum Robust Control: Algorithm, Applications, and Experiments.

Robust control design for quantum systems has been recognized as a key task in quantum information technology, molecular chemistry, and atomic physics. In this paper, an improved differential evolution algorithm, referred to as multiple-samples and mixed-strategy DE (msMS_DE), is proposed to search robust fields for various quantum control problems. In msMS_DE, multiple samples are used for fitness evaluation and a mixed strategy is employed for the mutation operation. In particular, the msMS_DE algorithm is applied to the control problems of: 1) open inhomogeneous quantum ensembles and 2) the consensus goal of a quantum network with uncertainties. Numerical results are presented to demonstrate the excellent performance of the improved machine learning algorithm for these two classes of quantum robust control problems. Furthermore, msMS_DE is experimentally implemented on femtosecond (fs) laser control applications to optimize two-photon absorption and control fragmentation of the molecule CH2BrI. The experimental results demonstrate the excellent performance of msMS_DE in searching for effective fs laser pulses for various tasks.

Quantum optimal control of multiple weakly interacting molecular rotors in the time-dependent Hartree approximation.

We perform quantum optimal control simulations, based on the Time-Dependent Hartree (TDH) approximation, for systems of three to five dipole-dipole coupled OCS rotors. A control electric field is used to steer all of the individual rotors, arranged in chains and regular polygons in a plane, toward either identical or unique objectives. The goal is to explore the utility of the TDH approximation to model the field-induced dynamics of multiple interacting rotors in the weak dipole-dipole coupling regime. A stochastic hill climbing approach is employed to seek an optimal control field that achieves the desired objectives at a specified target time. We first show that multiple rotors in chain and polygon geometries can be identically oriented in the same direction; these cases do not significantly depend on the presence of the dipole-dipole interaction. Additionally, in particular geometrical arrangements, we demonstrate that individual rotors can be uniquely manipulated toward different objectives with the same field. Specifically, it is shown that for a three rotor chain, the two end rotors can be identically oriented in a specific direction while keeping the middle rotor in its ground state, and for an equilateral triangle, two rotors can be identically oriented in a specific direction while the third rotor is oriented in the opposite direction. These multirotor unique objective cases exploit the shape of the field in coordination with dipole-dipole coupling between the rotors. Comparisons to numerically exact calculations, utilizing the TDH-determined fields, are given for all optimal control studies involving systems of three rotors.

Nature's Shortcut to Protein Folding.

This Feature Article presents a view of the protein folding transition based on the hypothesis that Nature has built features within the sequences that enable a Shortcut to efficient folding. Nature's Shortcut is proposed to be the early establishment of a set of nonlocal weak contacts, constituting protein loops that significantly constrain regions of the collapsed disordered protein into a native-like low-resolution fluctuating topology of major sections of the backbone. Nature's establishment of this scaffold of nonlocal contacts is claimed to bypass what would otherwise be a nearly hopeless unaided search for the final three-dimensional structure in proteins longer than ∼100 amino acids. To support this main contention of the Feature Article, the loop hypothesis (LH) description of early folding events is experimentally tested with time-resolved Förster resonance energy transfer techniques for adenylate kinase, and the data are shown to be consistent with theoretical predictions from the sequential collapse model (SCM). The experimentally based LH and the theoretically founded SCM are argued to provide a unified picture of the role of nonlocal contacts as constituting Nature's Shortcut to protein folding. Importantly, the SCM is shown to reliably predict key nonlocal contacts utilizing only primary sequence information. This view on Nature's Shortcut is open to the protein community for further detailed assessment, including its practical consequences, by suitable application of advanced experimental and computational techniques.

Author Correction: Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.

The original version of this Article contained an error in the spelling of the author Daniel D. Liu, which was incorrectly given as Daniel Liu. This has now been corrected in both the PDF and HTML versions of the Article.

Peak Annotation and Verification Engine for Untargeted LC-MS Metabolomics.

Untargeted metabolomics can detect more than 10 000 peaks in a single LC-MS run. The correspondence between these peaks and metabolites, however, remains unclear. Here, we introduce a Peak Annotation and Verification Engine (PAVE) for annotating untargeted microbial metabolomics data. The workflow involves growing cells in 13C and 15N isotope-labeled media to identify peaks from biological compounds and their carbon and nitrogen atom counts. Improved deisotoping and deadducting are enabled by algorithms that integrate positive mode, negative mode, and labeling data. To distinguish metabolites and their fragments, PAVE experimentally measures the response of each peak to weak in-source collision induced dissociation, which increases the peak intensity for fragments while decreasing it for their parent ions. The molecular formulas of the putative metabolites are then assigned based on database searching using both m/ z and C/N atom counts. Application of this procedure to Saccharomyces cerevisiae and Escherichia coli revealed that more than 80% of peaks do not label, i.e., are environmental contaminants. More than 70% of the biological peaks are isotopic variants, adducts, fragments, or mass spectrometry artifacts yielding ∼2000 apparent metabolites across the two organisms. About 650 match to a known metabolite formula based on m/ z and C/N atom counts, with 220 assigned structures based on MS/MS and/or retention time to match to authenticated standards. Thus, PAVE enables systematic annotation of LC-MS metabolomics data with only ∼4% of peaks annotated as apparent metabolites.

Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.

Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-ß-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.

Predicting the location of the non-local contacts in α-synuclein.

In this paper, the Sequential Collapse Model (SCM) for protein folding pathways is applied to investigate the location of the non-local contacts in the intrinsically disordered state of α-synuclein, a protein implicated in the onset and spreading of several serious neurodegenerative diseases. The model relies on the entropic cost of forming protein loops due to self-crowding effects, and the protein sequence to determine contact location and stability. It is found that the model predicts the existence of several possible non-local contacts, and the location of the non-local contacts is consistent with existing experimental evidence. The bearing of these findings on the pathogenic mechanism and its regulation is discussed.

Shaped incoherent light for control of kinetics: Optimization of up-conversion hues in phosphors.

We propose a method for interactively controlling multi-species atomic and molecular systems with incoherent light. The technique is referred to as shaped incoherent light for control (SILC), which entails dynamically tailoring the spectrum of a broadband incoherent source to control atomic and molecular scale kinetics. Optimal SILC light patterns can be discovered with adaptive learning techniques where the system's observed response is fed back to the control for adjustment aiming to improve the objective. To demonstrate this concept, we optimized a SILC source to optimally control the evolving hue in near-IR to visible upconverting phosphors, which share many similarities with chemical reaction kinetics including non-linear behavior. Thus, the results suggest that SILC may be a valuable tool for the control of chemical kinetics with tailored incoherent light.