Molecular Level Properties Research Articles

Quantum-Chemistry Enabled AI for Materials Discovery for Energy Storage

A priori and reliable simulations can enable timely and cost-efficient design and discovery of materials for energy. Therefore, ‘Let’s Start from Computing’ is an optimal approach to initialize modern day R&D processes. In energy storage, beyond lithium-ion (BLI) research has the potential to revolutionize consumer electronics including portable and stationary power, transportation, and grid energy storage sectors. Multi-valent (Mg, Ca, Zn) energy storage or economically viable monovalent (Na, K) batteries, high-density metal-air, metal-sulfur batteries, or grid-storage systems are considered in the beyond lithium-ion research and development. All these R&D efforts require significant fundamental knowledge via a priori computations for materials discovery, property prediction, and optimization. Atomistic modeling when coupled with reliable Artificial Intelligence (AI) approaches can provide accurate insights to accelerate discovery of optimalelectrolytes, electrodes, and membranes for BLI systems to reduce the cost. Thus, coupled with AI and multi-scale simulations techniques, atomistic modeling can address prediction of molecular level properties of materials (redox potentials, solvation, spectroscopic, and reactivity) to down-select optimal materials or material combinations. In this presentation, I will describe some of our recent efforts in active learning coupled with large scale first principles simulations to down select/optimize desired molecules for flow battery technology. This concept can be utilized for design of experiments using autonomous experimentation. Additionally, I will describe some of our quantum chemistry-informed molecular property predictions redoxmers and liquid organic hydrogen carriers. In addition to molecules, I will present. A data driven approach to study longer time scale diffusion of ions for multivalent battery concepts. Figure 1

Effect of adlay seed extract on the level of neuroprotection gene expression in human nasal orbital mesenchymal stem cells

IntroductionStem cells have gained attention for their potential as a promising approach for generating neurotrophins and advancing cell-based therapies for retinal degenerative diseases such as glaucoma. This study aimed to explore how adlay seed extract impacts the gene expression of key components within the neuroprotection pathway (NGF, TRKB, MAPK, PI3K) in human nasal orbital adipocytes mesenchymal stem cells (OAMSCs). MethodsNasal OAMSCs, with a density of 106 cells/ 10 cm2, were subjected to a 24-hour exposure to adlay seed extracts (namely the methanolic (MeOH) and residual (Res) fractions at a concentration of 1 mg/ml). The control group received an identical medium without the extract at the same time and under the same circumstances. We measured the relative expression levels of nerve growth factor (NGF), tyrosine receptor kinase B (TRKB), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K) in the treated cells versus the control group using real-time polymerase chain reaction (PCR). ResultsOur data revealed that both the MeOH and Res extracts of adlay seed led to a significant upregulation of NGF in nasal OAMSCs. MeOH extract also led to the overexpression of TRKB (the gene coding for BDNF receptor) in OAMSCs, while the other genes understudy, were not altered. ConclusionsOur study highlighted initial documentation of the stimulating impact of adlay extract on the transcriptional level of neurotrophin NGF and the TRKB in nasal OAMSCs. We also showed that the extraction method could significantly affect the molecular-level properties of adlay. This preliminary study can pave the ground for future advancements in the treatment of retinal neurodegenerative disorders and glaucoma.

Comprehensive investigation of 2-methylquinolinium-5-sulphosalicylate monohydrate: Synthesis, characterization, multifaceted analysis of molecular structure, optical, and nonlinear optical properties

We introduce the synthesis and characterization of a novel molecular salt crystal, 2-methylquinolinium-5-sulphosalicylate monohydrate (MQSSA), obtained through an equimolar reaction between donors (D) and acceptors (A) employing crystal engineering principles. The resulting proton transfer complex, MQSSA, crystallized into a monoclinic crystal system with space group P21/C, as revealed by SCXRD analysis. Significant peaks observed in PXRD analysis confirmed the crystallinity and purity of the material. FT-IR and FT-Raman spectroscopy were employed to analyze various functional groups present in the molecule. UV–Vis-NIR spectroscopy provided insights into absorbance transmittance, lower cutoff wavelength, and optical band gap, suggesting it's suitability for diverse optical applications, while characteristic emission was identified using PL measurements. Thermal stability was assessed via TG-DTA and TG-DSC techniques. Nonlinear absorption coefficient (β), nonlinear refractive index (n2), and third-order nonlinear susceptibility (χ3) were quantified using the Z-scan technique. Hirshfeld surface analysis and fingerprint plots were utilized to gain insight into intermolecular interactions and atomic arrangements within the MQSSA crystal, emphasizing the roles of crystal structure in H...H and O...H/H...O interactions. Additionally, quantum computational methods were employed to evaluate various molecular-level electronic characteristics, including molecular orbitals, molecular electrostatic potential maps, and first and second-order nonlinear optical (NLO) polarizability, providing insights into the molecular-level NLO response properties.

Concentration Fluctuation/Microheterogeneity Duality Illustrated with Aqueous 1,4-Dioxane Mixtures.

The structural properties of aqueous 1-4 dioxane mixtures are studied by computer simulations of different water and dioxane force field models, from the perspective of illustrating the link between structural properties at the molecular level and measurable properties such as radiation scattering intensities and Kirkwood-Buff integrals (KBIs). A strategy to consistently correct the KBI obtained from simulations is proposed, which allows us to obtain the genuine KBI corresponding to a given pair of molecular species, in the entire concentration range, and without necessitating excessively large system sizes. The application of this method to the aqueous dioxane mixtures, with an all-atom CHARMM dioxane model and 2 water models, namely, SPC/E and TIP3P, allows one to understand the differences in the structure of the corresponding mixtures at the molecular level, particularly concerning the role of the water aggregates and its model dependence. This study allows us to characterize the dual role played by the concentration fluctuations and the domain segregation, particularly in what concerns the calculated X-ray spectra.

Characterization of Poultry Gelatins Prepared by a Biotechnological Method for Targeted Changes at the Molecular Level.

Chicken collagen is a promising raw material source for the production gelatins and hydrolysates. These can be prepared biotechnologically using proteolytic enzymes. By choosing the appropriate process conditions, such changes can be achieved at the molecular level of collagen, making it possible to prepare gelatins with targeted properties for advanced cosmetic, pharmaceutical, medical, or food applications. The present research aims to investigate model samples of chicken gelatins, focusing on: (i) antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azinobis-3-etylbenzotiazolin-6-sulfonic acid (ABTS); (ii) the distribution of molecular weights via gel permeation chromatography with refractometric detection (GPC-RID); (iii) functional groups and the configuration of polypeptide chains related to molecular-level properties using Fourier transform infrared spectroscopy (FTIR); (iv) the microbiological populations on sabouraud dextrose agar (SDA), plate count agar (PCA), tryptic soy agar (TSA), and violet red bile lactose (VRBL) using the matrix-assisted laser desorption ionization (MALDI) method. Antioxidant activity towards ABTS radicals was more than 80%; activity towards DPPH radicals was more than 69%. The molecular weights of all gelatin samples showed typical α-, β-, and γ-chains. FTIR analysis confirmed that chicken gelatins all contain typical vibrational regions for collagen cleavage products, Amides A and B, and Amides I, II, and III, at characteristic wavenumbers. A microbiological analysis of the prepared samples showed no undesirable bacteria that would limit advanced applications of the prepared products. Chicken gelatins represent a promising alternative to products made from standard collagen tissues of terrestrial animals.

New insight into the role of the self-assembly of heteroatom compounds in heavy oil viscosity enhancement.

Unveiling the role of heteroatom compounds in heavy oil viscosity is pivotal for finding targeted viscosity reduction methods to improve oil recovery. This research investigates the impact of heteroatoms in asphaltene molecules by utilizing quantum chemical calculations and molecular dynamics simulations to analyze their electrostatic potential characteristics, pairwise interactions, and dynamic behavior within realistic reservoirs. Heteroatom compounds can influence the molecular-level properties of asphaltenes and thus impact the macroscopic behavior of heavy oils. Research results suggest that the presence of ketone and aromatic rings in asphaltene molecules leads to the unrestricted movement of pi electrons due to their collective electronegativity. Two distinct configurations of asphaltene dimers, face-to-face, and edge-to-face, were observed. Intermolecular interactions were predominantly governed by van der Waals forces, highlighting their significant role in stabilizing asphaltene aggregates. The distribution of asphaltene molecules in the oil phase can be summarized as the "rebar-cement" theory. In the heteroatom-free system, the face-to-face peaks in the radial distribution function exhibit significantly reduced magnitudes compared to those in the heteroatom-containing system. This emphasizes the pivotal function of heteroatoms in connecting molecular components to form a more compact asphaltene structure, which may result in a higher viscosity of heavy oil. These findings give insight into the significance of heteroatoms in bridging molecular components and shaping the intricate structure of asphaltene and advance our understanding of heavy oil viscosity properties.

Molecular simulations of understanding the structure and separation thermodynamics of 5-Hydroxymethylfurfural from 1-Butyl-3-Methyl imidazolium tetrafluoroborate

The furfural-based compounds derived from biomass is proven to be reducing greenhouse gas emissions for sustainable chemical processes. 5-hydroxymethylfurfural (5-HMF) is a bio-renewable material that can serve as a significant platform chemical to produce biofuels, green polymers, solvents, etc. Ionic liquids (ILs) have shown promising reaction media to produce 5-HMF from glucose and fructose. However, there is a substantial challenge in separating the 5-HMF from the ILs. In this paper, we use an organic solvent tetrahydrofuran (THF) to understand the molecular level properties of 5-HMF from 1-butyl-3-methyl imidazolium tetra-fluoroborate [BMIM]+[BF4]− using all-atom molecular dynamics simulations. We have analyzed various intermolecular structures, and dynamic and separation thermodynamic properties. Our results show that with an increase in 5-HMF concentration, we observe a favorable intermolecular interaction between 5-HMF and THF compared to the interactions between 5-HMF and [BMIM]+. The 5-HMF presents the dominant intermolecular interactions with cations compared to the anions. The self-diffusion coefficient of 5-HMF shows a decrease in THF and an increase in [BMIM]+[BF4]− with the rise in 5-HMF concentration. The solvation free energy (ΔGsolv) values of 5-HMF in both IL and THF show less negative value with an increase in 5-HMF concentration. The transfer free energy (ΔGtransfer) of 5-HMF (from IL to THF) shows less positive values with an increase in 5-HMF concentration. Overall results presented in this work are promising for understanding the complex interactions between furfural-based compounds and ILs.

Deposition freezing, pore condensation freezing and adsorption: three processes, one description?

Abstract. Heterogeneous ice nucleation impacts the hydrological cycle and climate through affecting cloud microphysical state and radiative properties. Despite decades of research, a quantitative description and understanding of heterogeneous ice nucleation remains elusive. Parameterizations are either fully empirical or heavily rely on classical nucleation theory (CNT), which does not consider molecular-level properties of the ice-nucleating particles – which can alter ice nucleation rates by orders of magnitude through impacting pre-critical stages of ice nucleation. The adsorption nucleation theory (ANT) of heterogeneous droplet nucleation has the potential to remedy this fundamental limitation and provide quantitative expressions in particular for heterogeneous freezing in the deposition mode (the existence of which has even been questioned recently). In this paper we use molecular simulations to understand the mechanism of deposition freezing and compare it with pore condensation freezing and adsorption. Based on the results of our case study, we put forward the plausibility of extending the ANT framework to ice nucleation (using black carbon as a case study) based on the following findings: (i) the quasi-liquid layer at the free surface of the adsorbed droplet remains practically intact throughout the entire adsorption and freezing process; therefore, the attachment of further water vapor to the growing ice particles occurs through a disordered phase, similar to liquid water adsorption. (ii) The interaction energies that determine the input parameters of ANT (the parameters of the adsorption isotherm) are not strongly impacted by the phase state of the adsorbed phase. Thus, not only is the extension of ANT to the treatment of ice nucleation possible, but the input parameters are also potentially transferable across phase states of the nucleating phase at least for the case of the graphite/water model system.

Ocean-atmosphere interactions: Different organic components across Pacific and Southern Oceans

Sea spray aerosol (SSA) particles strongly influence clouds and climate but the potential impact of ocean microbiota on SSA fluxes is still a matter of active research. Here–by means of in situ ship-borne measurements–we explore simultaneously molecular-level chemical properties of organic matter (OM) in oceans, sea ice, and the ambient PM2.5 aerosols along a transect of 15,000 km from the western Pacific Ocean (36°13′N) to the Southern Ocean (75°15′S). By means of orbitrap mass spectrometry and optical characteristics, lignin-like material (24 ± 5 %) and humic material (57 ± 8 %) were found to dominate the pelagic Pacific Ocean surface, while intermediate conditions were observed in the Pacific-Southern Ocean waters. In the marine atmosphere, we found a gradient of features in the aerosol: lignin-like material (31 ± 9 %) dominating coastal areas and the pelagic Pacific Ocean, whereas lipid-like (23 ± 16 %) and protein-like (11 ± 10 %) OM controlled the sympagic Southern Ocean (sea ice-influence). The results of this study showed that the OM composition in the ocean, which changes with latitude, affects the OM in aerosol compositions in the atmosphere. This study highlights the importance of the global-scale OM monitoring of the close interaction between the ocean, sea ice, and the atmosphere. Sympagic primary marine aerosols in polar regions must be treated differently from other pelagic-type oceans.

Review on Some Confusion Produced by the Bicontinuous Microemulsion Terminology and Its Domains Microcurvature: A Simple Spatiotemporal Model at Optimum Formulation of Surfactant-Oil-Water Systems.

Fundamental studies have improved understanding of molecular-level properties and behavior in surfactant-oil-water (SOW) systems at equilibrium and under nonequilibrium conditions. However, confusion persists regarding the terms "microemulsion" and "curvature" in these systems. Microemulsion refers to a single-phase system that does not contain distinct oil or water droplets but at least four different structures with globular domains of nanometer size and sometimes arbitrary shape. The significance of "curvature" in such systems is unclear. At high surfactant concentrations (typically 30 wt % or more), a single phase zone has been identified in which complex molecular arrangements may result in light scattering. As surfactant concentration decreases, the single phase is referred to as a bicontinuous microemulsion, known as the middle phase in a Winsor III triphasic system. Its structure has been described as involving simple or multiple surfactant films surrounding more or less elongated excess oil and water phase globules. In cases where the system separates into two or three phases, known as Winsor I or II systems, one of the phases, containing most of the surfactant, is also confusedly referred to as the microemulsion. In this surfactant-rich phase, the only curved objects are micellar size structures that are soluble in the system and have no real interface but rather exchange surfactant molecules with the external liquid phase at an ultrafast pace. The use of the term "curvature" in the context of these complex microemulsion systems is confusing, particularly when applied to merged nanometer-size globular or percolating domains. In this work, we discuss the terms "microemulsion" and "curvature", and the most simple four-dimensional spatiotemporal model is proposed concerning SOW equilibrated systems near the optimum formulation. This model explains the motion of surfactant molecules due to Brownian movement, which is a quick and arbitrary thermal fluctuation, and limited to a short distance. The resulting observation and behavior will be an average in time and in space, leading to a permanent change in the local microcurvature of the aggregate, thus changing the average from micelle-like to inverse micelle-like order over an extremely short time. The term "microcurvature" is used to explain the small variations of globule size and indicates a close-to-zero mean curvature of the surfactant-containing film surface shape.

Polysiloxane-Based Liquid-like Layers for Reducing Polymer and Wax Fouling

Surface fouling occurs when undesired matter adheres and accumulates on a surface, resulting in a decrease or loss of functionality. Polymer and wax fouling can cause costly blockages to crude oil pipelines, clog jet fuel injectors, foul chemical reaction vessels, and significantly decrease the efficiency of heat exchangers. Fouling occurs in many forms but can be segmented based on adherent size, modulus, and chemical functionality. Depending on the foulant, surface design strategies can vary greatly. Few strategies exist to prevent the buildup of wax and polymers on surfaces. In this report, we investigate the potential of highly disordered, siloxane liquid-like layers as a strategy for reducing wax and polymer deposition. In our tests, it was found that the liquid-like layers developed here were able to reduce postadsorption roughness for polymer and wax by as much as 35- and 47-fold, respectively, when compared to the control. SFG was utilized to investigate the molecular-level interfacial properties for each of the modified surfaces to help understand the antifouling mechanism. The data showed that the likely higher grafting density and a large degree of random conformational freedom at the liquid-surface interface make the developed siloxane-covered surfaces energetically unfavorable for polymer and wax accretion.

Dissection of hubs and bottlenecks in a protein-protein interaction network

Analysis of degree centrality in conjunction with betweenness centrality of proteins in a human protein-protein interaction network revealed three categories of centrally important proteins: a) proteins with high degree and betweenness (hub-bottlenecks denoted as MX), b) proteins with high betweenness and low degree (non-hub-bottlenecks/pure bottlenecks denoted as PB) and c) proteins with high degree and low betweenness (hub-non-bottlenecks/pure hubs denoted as PH). When subjected to a detailed statistical analysis of their molecular-level properties, the proteins belonging to each of these categories were found to be associated with distinct canonical molecular properties, i.e., "molecular markers". The MX proteins are a) conformationally versatile, mainly comprising of essential proteins, b) the targets for interactions by the proteins of viral and bacterial pathogens, c) evolutionally constrained, involved in multiple pathways, enriched with disease genes and d) involved in the functions such as protein stabilization, phosphorylation, and mRNA slicing processes. PB proteins are a) enriched with extracellular and cancer-related proteins, b) enriched with the approved drug targets and c) involved in cell-cell signaling processes. Finally, PH are a) structurally versatile, b) enriched with essential proteins primarily involved in housekeeping processes (transcription and replication). The fact that the proteins belonging to these three categories form three distinct sets in terms of their molecular properties reveals the existence of trichotomy among hubs and bottlenecks, and this knowledge is of paramount importance while prioritizing protein targets for further studies such as drug design and disease association studies based on their network centrality values.

A monovalent selective anion exchange membrane made by poly(2,6-dimethyl-1,4-phenyl oxide) for bromide recovery

Bromide recovery from waste streams is crucial for both environmental and economic reasons. Membrane technology has shown great potential in achieving efficient ion separation, credited to the use of separation membranes with well-defined pore structure down to molecular level and surface charge properties. Herein, a class of novel anion exchange membranes (AEMs) was fabricated by brominated poly (2,6-dimethyl-1, 4-phenyl oxide) (BPPO) and different content of 4-hydroxy-1-methylpiperidine (HMP) via the chemical substitution reaction for Br- recovery. The resulting membrane (HMP@BPPO-0.1) had an ion exchange capacity of 1.69 mmol g−1, a water content of 14.4 %, a swelling rate of 4.7 %, a surface electrical resistance of 3.68 Ω cm2 and a limiting current density of 28.4 mA cm−2. In addition, under a constant voltage of 15.0 V for 180 min in electrodialysis, the removal ratio of NaBr solution was 98.15 %, which was higher than that of the commercial AEM (ASE) (97.1 %) under the same testing conditions. To evaluate the Br- selectivity, the membranes were tested for an initial concentration of 50 mM of NaCl, NaBr and Na2SO4 in a mixed solution with a constant current density of 2.5 mA cm−2, 5.0 mA cm−2 and 10.0 mA cm−2. The results showed that the permselectivity of the HMP@BPPO-0.1 for 100 min was as high as 12.6 (Br-/SO42-) and 1.20 (Br-/Cl-) under the 5.0 mA cm−2 electric field, and the ion permeation rate of Cl-, Br- and SO42- were 0.78, 1.20 and 0.20 mol−1 m-2 h−1, respectively. Compared to the ASE membrane and the resulting membrane with negatively charged modification layer, this work suggests novel ideas in fabricating a membrane with Br- selectivity in view of resource recovery.

Stepping Beyond Cyclic Voltammetry: Obtaining the Electronic Properties of Electrified Solid-Liquid Interfaces

Organically tailorable monolayers of ferrocene-terminated alkanethiol self-assembled monolayers (Fc SAM, Fig. 1a) on Au surfaces are attractive model systems to elucidate the molecular-level physicochemical properties of solid-liquid electrochemical (EC) interfaces [1]. In particular, Fc SAM has been shown to be an attractive spectroscopic molecular probe for photoelectron spectroscopy because the Fe heteroatom is at a fixed position above the electrode surface. Thus, this allows photoelectron spectroscopy to ascertain the electronic and structural properties at a fixed position above the electrode surface [2-3]. The ability to obtain molecular-level structure-function-property relationships with Fc SAM has relevance to bio(chemical) sensors, micro-actuators, and molecular electronics.Here, we use X-ray and ultraviolet photoelectron spectroscopy combined with an electrochemical cell (EC-XPS/UPS) to electrochemically control the Fc SAM and spectroscopically probe the corresponding electronic and structural changes [2-3]. To perform our experiments, electrochemical (EC) measurements are performed in a separate and dedicated EC chamber in a solution environment under Ar atmosphere, followed by evacuation and finally transfer to the XPS/UPS analysis chamber [2-3]. The EC chamber contains a retractable PTFE (polytetrafluorethylene) cell and utilizes a hanging meniscus setup. I will discuss the merits and challenges of EC-XPS/UPS methodology in the context of other approaches.Using EC-XPS/UPS, we are able to discriminate anion dependencies (Fig. 1b-d) with respect to the Fe oxidation state, monolayer thickness, and changes to the valence structure regarding the highest occupied molecular orbital (HOMO. Lastly, we are able to spectroscopically probe the changes relating to the interfacial potential distribution across the electrode-monolayer-electrolyte interface or so-called “potential drop” in the form of systematic potential-induced binding energy shifts in the XPS/UPS spectra. Further details will be provided at the presentation. Fig. 1 (a) Ferrocene-terminated alkanethiol SAM on Au. Schematic of electrode-monolayer-electrolyte interface and interfacial potential distribution. (b) Cyclic voltammograms at 50 mV s-1 in 0.1 M NaTFSI or NaPF6 (c-d) Fe 2p3/2 spectra of Fc SAM, pristine and after anodic/cathodic polarization at 0.625 and 0 V, respectively.

DNA topology dictates emergent bulk elasticity and hindered macromolecular diffusion in DNA-dextran composites

Polymer architecture plays critical roles in both bulk rheological properties and microscale macromolecular dynamics in entangled polymer solutions and composites. Ring polymers, in particular, have been the topic of much debate due to the inability of the celebrated reptation model to capture their observed dynamics. Macrorheology and differential dynamic microscopy (DDM) are powerful methods to determine entangled polymer dynamics across scales; yet, they typically require different samples under different conditions, preventing direct coupling of bulk rheological properties to the underlying macromolecular dynamics. Here, we perform macrorheology on composites of highly overlapping DNA and dextran polymers, focusing on the role of DNA topology (rings versus linear chains) as well as the relative volume fractions of DNA and dextran. On the same samples under the same conditions, we perform DDM and single-molecule tracking on embedded fluorescent-labeled DNA molecules immediately before and after bulk measurements. We show DNA-dextran composites exhibit unexpected nonmonotonic dependences of bulk viscoelasticity and molecular-level transport properties on the fraction of DNA comprising the composites, with characteristics that are strongly dependent on the DNA topology. We rationalize our results as arising from stretching and bundling of linear DNA versus compaction, swelling, and threading of rings driven by dextran-mediated depletion interactions.

A theory of synaptic transmission.

Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters within just milliseconds of the action potential. Yet neurotransmitter release lacks a theoretical framework that is both phenomenologically accurate and mechanistically realistic. Here, we present an analytic theory of the action-potential-triggered neurotransmitter release at the chemical synapse. The theory is demonstrated to be in detailed quantitative agreement with existing data on a wide variety of synapses from electrophysiological recordings in vivo and fluorescence experiments in vitro. Despite up to ten orders of magnitude of variation in the release rates among the synapses, the theory reveals that synaptic transmission obeys a simple, universal scaling law, which we confirm through a collapse of the data from strikingly diverse synapses onto a single master curve. This universality is complemented by the capacity of the theory to readily extract, through a fit to the data, the kinetic and energetic parameters that uniquely identify each synapse. The theory provides a means to detect cooperativity among the SNARE complexes that mediate vesicle fusion and reveals such cooperativity in several existing data sets. The theory is further applied to establish connections between molecular constituents of synapses and synaptic function. The theory allows competing hypotheses of short-term plasticity to be tested and identifies the regimes where particular mechanisms of synaptic facilitation dominate or, conversely, fail to account for the existing data for the paired-pulse ratio. The derived trade-off relation between the transmission rate and fidelity shows how transmission failure can be controlled by changing the microscopic properties of the vesicle pool and SNARE complexes. The established condition for the maximal synaptic efficacy reveals that no fine tuning is needed for certain synapses to maintain near-optimal transmission. We discuss the limitations of the theory and propose possible routes to extend it. These results provide a quantitative basis for the notion that the molecular-level properties of synapses are crucial determinants of the computational and information-processing functions in synaptic transmission.

Interfacial Vibrational Spectroscopy of the Water Bending Mode on Ice Ih

We study the molecular-level properties of the single-crystal ice Ih surface using interface-specific sum frequency generation spectroscopy. We probe the water vibrational bend region around 1650 cm–1 of the basal plane of hexagonal ice to understand the interfacial structure from vibrational properties. As opposed to the stretch mode of ice, the bending mode response depends very weakly on temperature. The large line width of the bending mode response, relative to the response on water, is inconsistent with inhomogeneous broadening and points to ultrafast pure dephasing. The bending mode of ice provides an excellent means to study adsorbate–ice interactions and understand differences in ice and water reactivity.

Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants.

The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements.

Tracking Ultrafast Structural Dynamics by Time-Domain Raman Spectroscopy.

In traditional Raman spectroscopy, narrow-band light is irradiated on a sample, and its inelastic scattering, i.e., Raman scattering, is detected. The energy difference between the Raman scattering and the incident light corresponds to the vibrational energy of the molecule, providing the Raman spectrum that contains rich information about the molecular-level properties of the materials. On the other hand, by using ultrashort optical pulses, it is possible to induce Raman-active coherent nuclear motion of the molecule and to observe the molecular vibration in real time. Moreover, this time-domain Raman measurement can be combined with femtosecond photoexcitation, triggering chemical changes, which enables tracking ultrafast structural dynamics in a form of “time-resolved” time-domain Raman spectroscopy, also known as time-resolved impulsive stimulated Raman spectroscopy. With the advent of stable, ultrashort laser pulse sources, time-resolved impulsive stimulated Raman spectroscopy now realizes high sensitivity and a wide detection frequency window from THz to 3000 cm–1, and has seen success in unveiling the molecular mechanisms underlying the efficient functions of complex molecular systems. In this Perspective, we overview the present status of time-domain Raman spectroscopy, particularly focusing on its application to the study of femtosecond structural dynamics. We first explain the principle and a brief history of time-domain Raman spectroscopy and then describe the apparatus and recent applications to the femtosecond dynamics of complex molecular systems, including proteins, molecular assemblies, and functional materials. We also discuss future directions for time-domain Raman spectroscopy, which has reached a status allowing a wide range of applications.

Metabolic response to point mutations reveals principles of modulation of in vivo enzyme activity and phenotype

The relationship between sequence variation and phenotype is poorly understood. This is largely due to its complexity, as mutations are pleiotropic and affect several layers of cellular hierarchy, from molecular properties to systems level to the phenotype. Though mapping of phenotype to molecular, cellular and certain systems level properties has been elucidated in some systems, a precise mechanistic understanding of how metabolic perturbations arising out of mutations affect phenotype is lacking. Here we use metabolomic analysis to elucidate the molecular mechanism underlying the filamentous phenotype of E. coli strains that carry destabilizing mutations in the Dihydrofolate Reductase (DHFR). We find that partial loss of DHFR activity causes SOS response indicative of DNA damage and cell filamentation. This phenotype is triggered by an imbalance in deoxy nucleotide levels, most prominently a disproportionate drop in the intracellular dTTP. However, dTTP levels could not be explained by drop in dTMP based on the Michaelis-Menten like in vitro activity curve of Thymidylate Kinase (Tmk), an enzyme downstream of DHFR that phosphorylates dTMP to dTDP. Instead, we show that a highly cooperative (Hill coefficient 2.5) in vivo activity of Tmk is the cause of suboptimal dTTP levels. dTMP supplementation in the media rescues filamentation and restores in vivo Tmk kinetics to almost perfect Michaelis-Menten. The cooperative enzyme activity is best explained by the fractal nature of Tmk activity in vivo due to diffusion-limitation of substrate dTMP, possibly due to substrate channeling and metabolon formation. Overall, this study highlights the important role of cellular environment in sculpting enzyme kinetics. It also demonstrates the use of a systems level property of the cell – metabolome – as a stepping-stone to illustrate precise biophysical and biochemical mechanisms to bridge the multi-scale genotype-phenotype relationship.