Molecular Gas-Phase Conformational Ensembles.

Accurately determining the global minima of a molecular structure is important in diverse scientific fields, including drug design, materials science, and chemical synthesis. Conformational search engines serve as valuable tools for exploring the extensive conformational space of molecules and for identifying energetically favorable conformations. In this study, we present a comparison of Auto3D, CREST, Balloon, and ETKDG (from RDKit), which are freely available conformational search engines, to evaluate their effectiveness in locating global minima. These engines employ distinct methodologies, including machine learning (ML) potential-based, semiempirical, and force field-based approaches. To validate these methods, we propose the use of collisional cross-section (CCS) values obtained from ion mobility-mass spectrometry studies. We hypothesize that experimental gas-phase CCS values can provide experimental evidence that we likely have the global minimum for a given molecule. To facilitate this effort, we used our gas-phase conformation library (GPCL) which currently consists of the full ensembles of 20 small molecules and can be used by the community to validate any conformational search engine. Further members of the GPCL can be readily created for any molecule of interest using our standard workflow used to compute CCS values, expanding the ability of the GPCL in validation exercises. These innovative validation techniques enhance our understanding of the conformational landscape and provide valuable insights into the performance of conformational generation engines. Our findings shed light on the strengths and limitations of each search engine, enabling informed decisions for their utilization in various scientific fields, where accurate molecular structure determination is crucial for understanding biological activity and designing targeted interventions. By facilitating the identification of reliable conformations, this study significantly contributes to enhancing the efficiency and accuracy of molecular structure determination, with particular focus on metabolite structure elucidation. The findings of this research also provide valuable insights for developing effective workflows for predicting the structures of unknown compounds with high precision.

Nonlinear optical phase shift in blood plasmas for neoplasia diagnosis.

Detecting cancer at an early stage is crucial for timely treatment and better chances of survival. This research focuses on a scanning method for detecting cancer by examining the nonlinear optical characteristics of blood plasma samples. The study used both cancerous and noncancerous plasma samples and presented the results statistically by utilizing an incident laser power-dependent nonlinear optical phase shift variable called ζ in the Z-scan technique. The results showed a clear difference between the cancerous and non-cancerous samples with an accuracy of 92%. Furthermore, the study suggests the potential for measuring the cancer staging from the cancerous plasma. The study also confirmed a significant difference in ζ for plasma samples undergoing chemotherapy. A red laser with high power (above 18mW) was used to avoid the involvement of fluorophores or other chemical reagents in the plasma samples during the measurement.

Rapid and Automated Ab Initio Metabolite Collisional Cross Section Prediction from SMILES Input.

We implemented an ab initio CCS prediction workflow which incrementally refines generated structures using molecular mechanics, a deep learning potential, conformational clustering, and quantum mechanics (QM). Automating intermediate steps for a high performance computing (HPC) environment allows users to input the SMILES structure of small organic molecules and obtain a Boltzmann averaged collisional cross section (CCS) value as output. The CCS of a molecular species is a metric measured by ion mobility spectrometry (IMS) which can improve annotation of untargeted metabolomics experiments. We report only a minor drop in accuracy when we expedite the CCS calculation by replacing the QM geometry refinement step with a single-point energy calculation. Even though the workflow involves stochastic steps (i.e., conformation generation and clustering), the final CCS value was highly reproducible for multiple iterations on L-carnosine. Finally, we illustrate that the gas phase ensembles modeled for the workflow are intermediate files which can be used for the prediction of other properties such as aqueous phase nuclear magnetic resonance chemical shift prediction. The software is available at the following link: https://github.com/DasSusanta/snakemake_ccs.

Quantum Chemistry Calculations for Metabolomics.

A primary goal of metabolomics studies is to fully characterize the small-molecule composition of complex biological and environmental samples. However, despite advances in analytical technologies over the past two decades, the majority of small molecules in complex samples are not readily identifiable due to the immense structural and chemical diversity present within the metabolome. Current gold-standard identification methods rely on reference libraries built using authentic chemical materials ("standards"), which are not available for most molecules. Computational quantum chemistry methods, which can be used to calculate chemical properties that are then measured by analytical platforms, offer an alternative route for building reference libraries, i.e., in silico libraries for "standards-free" identification. In this review, we cover the major roadblocks currently facing metabolomics and discuss applications where quantum chemistry calculations offer a solution. Several successful examples for nuclear magnetic resonance spectroscopy, ion mobility spectrometry, infrared spectroscopy, and mass spectrometry methods are reviewed. Finally, we consider current best practices, sources of error, and provide an outlook for quantum chemistry calculations in metabolomics studies. We expect this review will inspire researchers in the field of small-molecule identification to accelerate adoption of in silico methods for generation of reference libraries and to add quantum chemistry calculations as another tool at their disposal to characterize complex samples.

AutoGraph: Autonomous Graph-Based Clustering of Small-Molecule Conformations.

While accurately modeling the conformational ensemble is required for predicting properties of flexible molecules, the optimal method of obtaining the conformational ensemble appears as varied as their applications. Ensemble structures have been modeled by generation, refinement, and clustering of conformations with a sufficient number of samples. We present a conformational clustering algorithm intended to automate the conformational clustering step through the Louvain algorithm, which requires minimal hyperparameters and importantly no predefined number of clusters or threshold values. The conformational graphs produced by this method for O-succinyl-l-homoserine, oxidized nicotinamide adenine dinucleotide, and 200 representative metabolites each preserved the geometric/energetic correlation expected for points on the potential energy surface. Clustering based on these graphs provides partitions informed by the potential energy surface. Automating conformational clustering in a workflow with AutoGraph may mitigate human biases introduced by guess and check over hyperparameter selection while allowing flexibility to the result by not imposing predefined criteria other than optimizing the model's loss function. Associated codes are available at https://github.com/TanemuraKiyoto/AutoGraph.

Metabolite Structure Assignment Using In Silico NMR Techniques.

A major challenge for metabolomic analysis is to obtain an unambiguous identification of the metabolites detected in a sample. Among metabolomics techniques, NMR spectroscopy is a sophisticated, powerful, and generally applicable spectroscopic tool that can be used to ascertain the correct structure of newly isolated biogenic molecules. However, accurate structure prediction using computational NMR techniques depends on how much of the relevant conformational space of a particular compound is considered. It is intrinsically challenging to calculate NMR chemical shifts using high-level DFT when the conformational space of a metabolite is extensive. In this work, we developed NMR chemical shift calculation protocols using a machine learning model in conjunction with standard DFT methods. The pipeline encompasses the following steps: (1) conformation generation using a force field (FF)-based method, (2) filtering the FF generated conformations using the ASE-ANI machine learning model, (3) clustering of the optimized conformations based on structural similarity to identify chemically unique conformations, (4) DFT structural optimization of the unique conformations, and (5) DFT NMR chemical shift calculation. This protocol can calculate the NMR chemical shifts of a set of molecules using any available combination of DFT theory, solvent model, and NMR-active nuclei, using both user-selected reference compounds and/or linear regression methods. Our protocol reduces the overall computational time by 2 orders of magnitude over methods that optimize the conformations using fully ab initio methods, while still producing good agreement with experimental observations. The complete protocol is designed in such a manner that makes the computation of chemical shifts tractable for a large number of conformationally flexible metabolites.

Superwavelength, wavelength, and subwavelength laser-induced periodic surface structures on zinc and their energy-dispersive x-ray analysis.

In this work, we demonstrated simultaneous generation of three types of laser-induced periodic surface structures (LIPSSs) on a metal surface by processing Zn with a linearly polarized femtosecond laser pulse of 100 fs duration at a wavelength of 800 nm. In the center of the laser-processed region (a line), the period was found to be as high as 1470 nm (superwavelength LIPSS), whereas at the outer region, the LIPSS period was found to be as small as 200 nm (subwavelength LIPSS). In between these two regions, the LIPSSs were found to have period of 800 nm (wavelength LIPSS). In the energy-dispersive x-ray (EDX) study, the Zn:O atomic ratio was found to be 70%∶30% in the LIPSS-containing region. In contrast to this, in the region containing no LIPSS, the Zn:O atomic ratio was found to be 90%:10%. Discussion is given on the significance of the observed LIPSS, in terms of their possible growth mechanism and comparison with previously published results.

Nucleoside-2',3'/3',5'-bis(thio)phosphate antioxidants are also capable of disassembly of amyloid beta42-Zn(ii)/Cu(ii) aggregates via Zn(ii)/Cu(ii)-chelation.

Currently, there is an urgent need for biocompatible metal-ion chelators capable of antioxidant activity and disassembly of amyloid beta (Aß)-aggregates as potential therapeutics for Alzheimer's disease (AD). We recently demonstrated the promising antioxidant activity of adenine/guanine 2',3' or 3',5'-bis(thio)phosphate analogues, 2'-dA/G3'5'PO/S and A2'3'PO/S, and their affinity to Zn(ii)-ions. These findings encouraged us to evaluate them as agents for the dissolution of Aß42-Zn(ii)/Cu(ii) aggregates. Specifically, we explored their ability to bind Cu(ii)/Zn(ii)-ions, the geometry and stoichiometry of these complexes, Cu(ii)/Zn(ii)-binding-sites and binding mode, and the ability of these analogues to dissolve Aß42-Zn(ii)/Cu(ii) aggregates, as well as their effect on the secondary structure of those aggregates. Finally, we identified the most promising agents for dissolution of Aß42-Zn(ii)/Cu(ii) aggregates. Specifically, we observed the formation of a 1 : 1 complex between 2'-dG3'5'PO and Cu(ii), involving O4 ligands. Zn(ii) was coordinated by both thiophosphate groups of 2'-dA3'5'PS and A2'3'PS involving O2S2 ligands in a 1 : 1 stoichiometry. A2'3'PS dissolves Aß42-Zn(ii) and Aß42-Cu(ii) aggregates as effectively as, and 2.5-fold more effectively than EDTA, respectively. Furthermore, 2'-dG3'5'PS and A2'3'PS reverted the Aß42-M(ii) structure, back to that of the free Aß42. Finally, cryo-TEM and TEM images confirmed the disassembly of Aß42 and Aß42-M(ii) aggregates by A2'3'PS. Hence, 2'-dG3'5'PS and A2'3'PS may serve as promising scaffolds for new AD therapeutics, acting as both effective antioxidants and agents for solubilization of Aß42-Cu(ii)/Zn(ii) aggregates.

First principles model calculations of the biosynthetic pathway in selinadiene synthase.

Terpenes comprise the largest class of natural products currently known. These ubiquitous molecules are synthesized by terpene synthases via complex carbocationic reactions, incorporating highly reactive intermediates. In the current study, we present a mechanistic investigation of the biosynthetic pathway for the formation of selina-4(15),7(11)-diene. We employ density functional theory to study a model carbocation system in the gas-phase, and delineate the energetic feasibility of a plausible reaction path. Our results suggests that during formation of selina-4(15),7(11)-diene, the substrate is likely folded in a conformation conducive to sequential cyclizations. We propose that a required proton transfer cannot occur intramolecularly in the gas-phase due to a high free energy barrier, and that enzyme assistance is essential for this step. Hybrid quantum mechanics-molecular mechanics docking studies suggest that enzyme intervention could be realized through electrostatic guidance.

Electron Detachment and Subsequent Structural Changes of Water Clusters.

A cost-effective equation of motion coupled cluster method, EOMIP-CCSD(2), is used to investigate vertical and adiabatic ionization potential as well as ionization-induced structural changes of water clusters and compared with CCSD(T), CASPT2, and MP2 methods. The moderate N(5) scaling and low storage requirement yields EOMIP-CCSD(2) calculation feasible even for reasonably large molecules and clusters with accuracy comparable to CCSD(T) method at much cheaper computational cost. Our calculations shed light on the authenticity of EOMIP-CCSD(2) results and establish a reliable method to study of ionization energy of molecular clusters. We have further investigated the performance of several classes of DFT functionals for ionization energies of water clusters to benchmark the results and to get a reliable functionals for the same.

Understanding the site selectivity in small-sized neutral and charged Al(n) (4 ≤ N ≤ 7) clusters using density functional theory based reactivity descriptors: a validation study on water molecule adsorption.

Aluminum clusters are now technologically important due to their high catalytic activity. Our present study on the small-sized aluminum clusters applies density functional theory (DFT)-based reactivity descriptors to identify potential sites for adsorption and eventual chemical reaction. Depending on symmetry, susceptibility of various type of reactive sites within a cluster toward an impending electrophilic and/or nucleophilic attack is predicted using the reactivity descriptors. In addition, the study devises general rules as to how the size, shape, and charge of the cluster influences the number of available sites for an electrophilic and/or nucleophilic attack. The predictions by reactivity descriptors are validated by performing an explicit adsorption of water molecule on Al clusters with four atoms. The adsorption studies demonstrate that the most stable water-cluster complex is obtained when the molecule is adsorbed through an oxygen atom on the site with the highest relative electrophilicity.

Critical study of the charge transfer parameter for the calculation of interaction energy using the local hard-soft acid-base principle.

Local hard-soft acid-base (HSAB) principle is semiquantitative in nature due to the presence of an ad hoc charge transfer parameter. The accuracy of HSAB principle significantly depends on the definition of this ad hoc parameter. In this paper, for the first time we have introduced the second-order approximation of ΔN (ΔNsecond) as an ad hoc parameter for charge transfer to calculate interaction energies of multiple site based interactions using local hard soft acid base principle. The second-order approximation of ΔN has been derived from Sanderson's electronegativity equalization principle. To validate our approach, we have studied interaction energies of some prototype molecules. The interaction energies obtained from our approach have been further compared with the interaction energies of those obtained using other charge transfer parameters (ΔNfirst and λ) and the conventional methods. We have also discussed the advantages and limitations of the approach.

Reconfigurable wavefront sensor for ultrashort pulses.

A highly flexible Shack-Hartmann wavefront sensor for ultrashort pulse diagnostics is presented. The temporal system performance is studied in detail. Reflective operation is enabled by programming tilt-tolerant microaxicons into a liquid-crystal-on-silicon spatial light modulator. Nearly undistorted pulse transfer is obtained by generating nondiffracting needle beams as subbeams. Reproducible wavefront analysis and spatially resolved second-order autocorrelation are demonstrated at incident angles up to 50° and pulse durations down to 6 fs.

In Silico Collision Cross Section Calculations to Aid Metabolite Annotation.

The interpretation of ion mobility coupled to mass spectrometry (IM-MS) data to predict unknown structures is challenging and depends on accurate theoretical estimates of the molecular ion collision cross section (CCS) against a buffer gas in a low or atmospheric pressure drift chamber. The sensitivity and reliability of computational prediction of CCS values depend on accurately modeling the molecular state over accessible conformations. In this work, we developed an efficient CCS computational workflow using a machine learning model in conjunction with standard DFT methods and CCS calculations. Furthermore, we have performed Traveling Wave IM-MS (TWIMS) experiments to validate the extant experimental values and assess uncertainties in experimentally measured CCS values. The developed workflow yielded accurate structural predictions and provides unique insights into the likely preferred conformation analyzed using IM-MS experiments. The complete workflow makes the computation of CCS values tractable for a large number of conformationally flexible metabolites with complex molecular structures.

Highly efficient THG in TiO2 nanolayers for third-order pulse characterization.

Third harmonic generation (THG) of femtosecond laser pulses in sputtered nanocrystalline TiO2 thin films is investigated. Using layers of graded thickness, the dependence of THG on the film parameters is studied. The maximum THG signal is observed at a thickness of 180 nm. The corresponding conversion efficiency is 26 times larger compared to THG at the air-glass interface. For a demonstration of the capabilities of such a highly nonlinear material for pulse characterization, third-order autocorrelation and interferometric frequency-resolved optical gating (IFROG) traces are recorded with unamplified nanojoule pulses directly from a broadband femtosecond laser oscillator.

Extended-area nanostructuring of TiO2 with femtosecond laser pulses at 400 nm using a line focus.

An efficient way to generate nanoscale laser-induced periodic surface structures (LIPSS) in rutile-type TiO(2) with frequency-converted femtosecond laser pulses at wavelengths around 400 nm is reported. Extended-area structuring on fixed and moving substrates was obtained by exploiting the line focus of a cylindrical lens. Under defined conditions with respect to pulse number, pulse energy and scanning velocity, two types of ripple-like LIPSS with high and low spatial frequencies (HSFL, LSFL) with periods in the range of 90 nm and 340 nm, respectively, were formed. In particular, lower numbers of high energetic pulses favour the generation of LSFL whereas higher numbers of lower energetic pulses enable the preferential creation of HSFL. Theoretical calculations on the basis of the Drude model support the assumption that refractive index changes by photo-excited carriers are a major mechanism responsible for LSFL. Furthermore, the appearance of random substructures as small as 30 nm superimposing low spatial frequency ripples is demonstrated and their possible origin is discussed.

Soil erodibility indices under different land uses in Ri-Bhoi district of Meghalaya (India).

In absence of soil erosion plots for determination of erodibility index (K) for erosion models like Universal Soil Loss Equation (USLE) or Revised Universal Soil Loss Equation (RUSLE) to estimate soil erosion, empirical relations are used. In the present study, soil erodibility index was determined for entire Ri-bhoi district of Meghalaya based on soil physical and chemical properties through empirical relationship and presented in a map form. Dominant land uses of the district were identified through geo-spatial tools which were viz. agriculture, forest, jhum land and wasteland. Soil samples from surface depth (01-15 cm) were collected from areas of different dominant land uses. Twenty five sampling points were selected under each land use type and geo-coded them on the base map of Ri-bhoi district. Apart from K-index, Clay Ratio, Modified Clay Ratio and Critical Soil Organic Matter were also determined for understanding the effect of primary soil particles on erodibility. In agriculture land use system K-index values were found in the range of 0.08-0.41 with an average of 0.25 ± 0.02. In case of jhum, forest and wasteland these were in the range of 0.08-0.42 with an average of 0.20 ± 0.01; 0.09-0.40 with an average of 0.22 ± 0.02, and 0.10-0.34 with an average value of 0.23 ± 0.02, respectively. Clay ratio (2.74) and Modified clay ratio (2.41) were observed to be higher in forest LUS, lower clay ratio (1.97) and modified clay ratio (1.81) were found in the wasteland indicating erosion susceptibility in forested area. The values of Critical Level of Organic Matter (CLOM) for the district ranged from 4.72 to 16.56. Out of 100 samples, only one sample had CLOM value less than 5 and rest 99 samples had values more than 5 indicating that the soils of the district had moderate to stable soil structure and offer resistance to erosion. All the indices values of geo-coded points were then interpolated in the Arc-GIS environment to produce land use based maps for Ri-bhoi district of Meghalaya. As K-index is a quantitative parameter which is used in models, the index can be then interpolated for estimation of soil erosion through USLE or RUSLE for any given situation.

Nonlinearly coupled, gain-switched Nd:YAG second harmonic laser with variable pulse width.

An all-solid-state, gain-switched, green laser is developed using a side diode-array pumped Nd:YAG laser and a KTiOPO(4) (KTP) crystal as an intracavity frequency doubler. The effect of nonlinear coupling on the pulse width of the fundamental is studied and is found to be in good agreement with the experimental measurement. In this preliminary experiment, a peak power of 40 W at 532 nm corresponding to a pulse width of 409 ns is obtained for an average pump power of 2 W. Compared to a Q-switched laser, it is simple and does not require a high voltage RF driver or saturable absorbers in its operation. The laser may be useful where relatively longer nanosecond pulses are required such as eye surgery, micromachining, and underwater communication.

A comparative study between the outcomes of visual internal urethrotomy for short segment anterior urethral strictures done under spinal anesthesia and local anesthesia.

OBJECTIVE: This study is a randomized controlled study comparing the effectiveness and outcomes of direct visual inter urethrotomy (DVIU) for short segment anterior urethral strictures performed under local anesthesia versus spinal anesthesia. MATERIAL AND METHODS: Patients presenting with an anterior urethral stricture up to 2 cm were randomized into two interventional groups: Group I-DVIU done under spinal anesthesia and Group II-DVIU performed under local anesthesia. Procedural discomfort was analyzed with a visual analog scale (VAS) immediately postoperatively and after one hour of the procedure. The changes in the vital parameters (systolic blood pressure and pulse rate) were recorded. The success of the procedure was defined as the absence of symptoms of recurrent stricture along with the ability of self-urethral calibration with an 18Fr catheter on follow-up. RESULTS: One hundred and twenty patients, between December 2015 and February 2017, were randomized into the two above-mentioned groups with 60 patients each. The demographic profile, the stricture characteristics (etiology, length, and duration of symptoms), and the preoperative parameters (Qmax, preoperative pulse rate, and systolic blood pressures) were comparable in both the groups. The mean (±SD) intraoperative and one-hour postoperative VAS scores were 1.96 (±1.04) and 1.20 (±0.73), respectively, for Group I, which were significantly less (p<0.05) than the VAS scores 4.26 (± 1.98) and 2.13 (±1.71), respectively, for Group II. The intraoperative mean increases in pulse rate and systolic blood pressure were also significantly lower in Group I (p<0.05). The change in postoperative Qmax (mL/sec) was comparable in both the groups (mean of 20.75±4.31 vs. 19.041 4.88) and so is the stricture free rate at a one-year follow-up. No significant differences in complication rates were observed in both the groups. CONCLUSION: Although perioperative procedural parameters seem to be in favor of spinal anesthesia, the outcome of DVIU is independent of the type of anesthesia used.

Distraction during cystoscopy to reduce pain and increase satisfaction: Randomized control study between real-time visualization versus listening to music versus combined music and real-time visualization.

PURPOSE: This study aims to compare the various distraction methods used during office cystoscopy to decrease pain and dissatisfaction among patients. MATERIALS AND METHODS: Two hundred patients undergoing rigid cystoscopy between January 2017 and July 2017 were randomized into four groups of 50 patients: (1) Group I: Patients who listened to music during the cystoscopy, (2) Group II: Patients allowed real-time visualization of the cystoscopy, (3) Group III: Patients who listened to music and had real-time visualization of the procedure, (4) Group IV: Control group undergoing cystoscopy without any distraction used. A visual analog scale (VAS) (1-10) was used for a self-assessment of pain, satisfaction, and willingness for repeat cystoscopy. RESULTS: Demographic characteristics, mean age, procedure duration, and procedure indications were statistically similar between the four groups. The mean VAS pain score were significantly lower in the three study Groups (I, II, and III) where distraction methods were used during cystoscopies as compared to the control Group IV (P < 0.001) and the satisfaction VAS scores and VAS scores for willingness to undergo a repeat procedure were significantly higher in the study groups (P < 0.001). Statistically significant decreased postprocedural pulse rate and blood pressure in comparison with to their preprocedural values were observed when distraction methods were used (P < 0.01). Patients undergoing cystoscopies listening to music and real-time visualization (Group III) had better VAS scores than the others (P < 0.01). CONCLUSIONS: Distraction methods reduce pain and increase satisfaction among patients. Best results are with combined listening to music and direct real-time visualization.