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Background: Quantitative real-time MRI-based temperature mapping techniques are hampered by abdominal motion. Intrascan motion can be reduced by rapid acquisition sequences such as 2D echo planar imaging (EPI), and inter-scan organ displacement can be compensated by image processing such as optical flow (OF) algorithms. However, motion field estimation can be seriously affected by local variation of signal intensity on magnitude images inherent to tissue heating, potentially leading to erroneous temperature estimates., Purpose: This study aims to characterize, in the context of clinical MRI-guided microwave ablation (MWA), a novel deformable image registration (DIR) algorithm that enhances the generation of thermal maps aligned to a reference position, a critical step for calculating cumulative thermal dose and, consequently, for the real-time evaluation of interventional procedure progress., Methods: A retrospective image analysis was performed on 11 patients that underwent MWA of a liver tumor (primary or metastasis). Ablation duration was set to 9 ± 2 min with a 14-gauge large antenna. A stack of 13-20 contiguous slices was acquired dynamically (350 repetitions) at 1.5T using a single-shot EPI sequence. Evaluation was first performed on motion-free datasets (5 gated acquisitions using a cushion positioned in the patient abdomen) then with ones with motion (8 fixed-frequency acquisitions at 0.5 Hz). Temperature, thermal dose and lesion size were computed using three workflows: (i) standard phase subtraction (gold standard), (ii) conventional OF motion compensation, (iii) PCA-based OF motion compensation. The impact of flow field, temperature and lesion volume estimation were compared using averaged endpoint error (AEE), NRMSE and bland Altman plot, respectively., Results: Intensity signal decreases (close to 50%) were observed in the vicinity of the probe during MW energy delivery. Both motion correction algorithms reduce the NRMSE of magnitude images throughout the acquisition (p < 0.005) and achieve similar results between them. Gated acquisition results. Conventional OF produced erroneous vector fields compared to the PCA-based OF, leading to higher maximal EE (3 mm vs. 1 mm) and temperature errors up to 15°C-20°C. PCA-based OF algorithm significantly reduces the NRMSE of temperature (p < 0.005). The conventional OF method underestimated the final size of lesions with a bias of 0.93 cm 3 while the PCA-based OF reported a bias of 0.5 cm 3 . Fixed frequency acquisition results. The temperature estimation without motion correction led to strong fluctuations or loss of temperature measurement while the proposed PCA-based OF recovered both a stable and precise measurement with null bias., Conclusion: The deformable image registration algorithm is less sensitive to local variations of the signal. Volumetric temperature imaging without gating (20 slices/2 s) could be performed with the same accuracy, and offer trade-offs in acquisition time or volume coverage. Such a strategy is expected to increase procedure safety by monitoring large volumes more rapidly for MR-guided thermotherapy on mobile organs., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: Clinical Laser-Induced Thermotherapy (LITT) currently lacks precise control of tissue temperature increase during the procedure. This study presents a new method to automatically regulate the maximum temperature increase in vivo at different positions by adjusting LITT power delivered by multiple laser probes using real-time volumetric MR-thermometry., Methods: The regulation algorithm was evaluated in vivo on a pig leg muscle. Temperature regulation was performed in volumes surrounding each laser probe tip. The power delivered to each laser probe was automatically adjusted every second using a feedback control algorithm by processing on-the-fly MR-thermometry images (10 slices/second) on a 1.5 T clinical scanner (1.56 mm × 1.56 mm x 3 mm resolution), using the proton-resonance frequency (PRF) shift technique. Several experimental conditions were tested with predefined temperature-time profiles corresponding to conditions of thermal ablation (+30 °C above body temperature) or moderate hyperthermia (+10 and + 15 °C). Control images were acquired after injection of Gadolinium at the end of experiment and were compared with the thermal dose images calculated from the thermometry images., Results: The mean difference and root mean squared error between target temperatures and measured ones remained below 0.5 °C and 2 °C respectively, for 5 min duration. Lesion sizes observed on thermal dose and on images acquired after gadolinium injection were in good agreement., Conclusion: Automatic regulation of in vivo temperature increase during LITT procedures with multiple laser emitters control is feasible. The method provides an adaptative solution to improve the safety and efficacity of such clinical procedures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Manon Desclides reports a relationship with Certis Therapeutics that includes: employment. Bruno Quesson reports a relationship with Certis Therapeutics that includes: consulting or advisory and equity or stocks. Valery Ozenne reports a relationship with Certis Therapeutics that includes: consulting or advisory and equity or stocks. Pierre Bour reports a relationship with Certis Therapeutics that includes: employment. Thibaut Faller reports a relationship with Certis Therapeutics that includes: employment. Stephane Chemouny reports a relationship with Certis Therapeutics that includes: employment and equity or stocks. Guillaume Machinet reports a relationship with ALPhANOV Optical and Laser Technological Centre that includes: employment. Christophe Pierre reports a relationship with ALPhANOV Optical and Laser Technological Centre that includes: employment. Julie Carcreff reports a relationship with ALPhANOV Optical and Laser Technological Centre that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Interventional magnetic resonance imaging (MRI) can provide a comprehensive setting for microwave ablation of tumors with real-time monitoring of the energy delivery using MRI-based temperature mapping. The purpose of this study was to quantify the accuracy of three-dimensional (3D) real-time MRI temperature mapping during microwave heating in vitro by comparing MRI thermometry data to reference data measured by fiber-optical thermometry., Methods: Nine phantom experiments were evaluated in agar-based gel phantoms using an in-room MR-conditional microwave system and MRI thermometry. MRI measurements were performed for 700 s (25 slices; temporal resolution 2 s). The temperature was monitored with two fiber-optical temperature sensors approximately 5 mm and 10 mm distant from the microwave antenna. Temperature curves of the sensors were compared to MRI temperature data of single-voxel regions of interest (ROIs) at the sensor tips; the accuracy of MRI thermometry was assessed as the root-mean-squared (RMS)-averaged temperature difference. Eighteen neighboring voxels around the original ROI were also evaluated and the voxel with the smallest temperature difference was additionally selected for further evaluation., Results: The maximum temperature changes measured by the fiber-optical sensors ranged from 7.3 K to 50.7 K. The median RMS-averaged temperature differences in the originally selected voxels ranged from 1.4 K to 3.4 K. When evaluating the minimum-difference voxel from the neighborhood, the temperature differences ranged from 0.5 K to 0.9 K. The microwave antenna and the MRI-conditional in-room microwave generator did not induce relevant radiofrequency artifacts., Conclusion: Accurate 3D real-time MRI temperature mapping during microwave heating with very low RMS-averaged temperature errors below 1 K is feasible in gel phantoms., Relevance Statement: Accurate MRI-based volumetric real-time monitoring of temperature distribution and thermal dose is highly relevant in clinical MRI-based interventions and can be expected to improve local tumor control, as well as procedural safety by extending the limits of thermal (e.g., microwave) ablation of tumors in the liver and in other organs., Key Points: Interventional MRI can provide a comprehensive setting for the microwave ablation of tumors. MRI can monitor the microwave ablation using real-time MRI-based temperature mapping. 3D real-time MRI temperature mapping during microwave heating is feasible. Measured temperature errors were below 1 °C in gel phantoms. The active in-room microwave generator did not induce any relevant radiofrequency artifacts., (© 2024. The Author(s).)

Precise control of tissue temperature during Laser-Induced Thermotherapy (LITT) procedures has the potential to improve the clinical efficiency and safety of such minimally invasive therapies. We present a method to automatically regulate in vivo the temperature increase during LITT using real-time rapid volumetric Magnetic Resonance thermometry (8 slices acquired every second, with an in-plane resolution of 1.4 mmx1.4 mm and a slice thickness of 3 mm) using the proton-resonance frequency (PRF) shift technique. The laser output power is adjusted every second using a feedback control algorithm (proportional-integral-derivative controller) to force maximal tissue temperature in the targeted region to follow a predefined temperature-time profile. The root-mean-square of the difference between the target temperature and the measured temperature ranged between 0.5 °C and 1.4 °C, for temperature increases between + 5 °C to + 30 °C above body temperature and a long heating duration (up to 15 min), showing excellent accuracy and stability of the method. These results were obtained on a 1.5 T clinical MRI scanner, showing a potential immediate clinical application of such a temperature controller during MR-guided LITT., (© 2023. The Author(s).)

Purpose: In presence of respiratory motion, temperature mapping is altered by in-plane and through-plane displacements between successive acquisitions together with periodic phase variations. Fast 2D Echo Planar Imaging (EPI) sequence can accommodate intra-scan motion, but limited volume coverage and inter-scan motion remain a challenge during free-breathing acquisition since position offsets can arise between the different slices., Method: To address this limitation, we evaluated a 2D simultaneous multi-slice EPI sequence with multiband (MB) acceleration during radiofrequency ablation on a mobile gel and in the liver of a volunteer (no heating). The sequence was evaluated in terms of resulting inter-scan motion, temperature uncertainty and elevation, potential false-positive heating and repeatability. Lastly, to account for potential through-plane motion, a 3D motion compensation pipeline was implemented and evaluated., Results: In-plane motion was compensated whatever the MB factor and temperature distribution was found in agreement during both the heating and cooling periods. No obvious false-positive temperature was observed under the conditions being investigated. Repeatability of measurements results in a 95% uncertainty below 2 °C for MB1 and MB2. Uncertainty up to 4.5 °C was reported with MB3 together with the presence of aliasing artifacts. Lastly, fast simultaneous multi-slice EPI combined with 3D motion compensation reduce residual out-of-plane motion., Conclusion: Volumetric temperature imaging (12 slices/700 ms) could be performed with 2 °C accuracy or less, and offer tradeoffs in acquisition time or volume coverage. Such a strategy is expected to increase procedure safety by monitoring large volumes more rapidly for MR-guided thermotherapy on mobile organs.

The complexity of the MRI protocol is one of the factors limiting the clinical adoption of MR temperature mapping for real-time monitoring of cardiac ablation procedures and a push-button solution would ease its use. Continuous gradient echo golden angle radial acquisition combined with intra-scan motion correction and undersampled temperature determination could be a robust and more user-friendly alternative than the ultrafast GRE-EPI sequence which suffers from sensitivity to magnetic field susceptibility artifacts and requires ECG-gating. The goal of this proof-of-concept work is to establish the temperature uncertainty as well as the spatial and temporal resolutions achievable in an Agar-gel phantom and in vivo using this method. GRE radial golden angle acquisitions were used to monitor RF ablations in a phantom and in vivo in two sheep hearts with different slice orientations. In each case, 2D rigid motion correction based on catheter micro-coil signal, tracking its motion, was performed and its impact on the temperature imaging was assessed. The temperature uncertainty was determined for three spatial resolutions (1 × 1 × 3 mm 3 , 2 × 2 × 3 mm 3 , and 3 × 3 × 3 mm 3 ) and three temporal resolutions (0.48, 0.72, and 0.97 s) with undersampling acceleration factors ranging from 2 to 17. The combination of radial golden angle GRE acquisition, simultaneous catheter tracking, intra-scan 2D motion correction, and undersampled thermometry enabled temperature monitoring in the myocardium in vivo during RF ablations with high temporal (< 1 s) and high spatial resolution. The temperature uncertainty ranged from 0.2 ± 0.1 to 1.8 ± 0.2 °C for the various temporal and spatial resolutions and, on average, remained superior to the uncertainty of an EPI acquisition while still allowing clinical monitoring of the RF ablation process. The proposed method is a robust and promising alternative to EPI acquisition to monitor in vivo RF cardiac ablations. Further studies remain required to improve the temperature uncertainty and establish its clinical applicability., (© 2022. The Author(s).)

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6  ×  6  ×  6 m 3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties., (© The Author(s) 2022.)

Purpose: To propose a MR-thermometry method and associated data processing technique to predict the maximal RF-induced temperature increase near an implanted wire for any other MRI sequence., Methods: A dynamic single shot echo planar imaging sequence was implemented that interleaves acquisition of several slices every second and an energy deposition module with adjustable parameters. Temperature images were processed in real time and compared to invasive fiber-optic measurements to assess accuracy of the method. The standard deviation of temperature was measured in gel and in vivo in the human brain of a volunteer. Temperature increases were measured for different RF exposure levels in a phantom containing an inserted wire and then a MR-conditional pacemaker lead. These calibration data set were fitted to a semi-empirical model allowing estimation of temperature increase of other acquisition sequences., Results: The precision of the measurement obtained after filtering with a 1.6x1.6 mm2 in plane resolution was 0.2°C in gel, as well as in the human brain. A high correspondence was observed with invasive temperature measurements during RF-induced heating (0.5°C RMSE for a 11.5°C temperature increase). Temperature rises of 32.4°C and 6.5°C were reached at the tip of a wire and of a pacemaker lead, respectively. After successful fitting of temperature curves of the calibration data set, temperature rise predicted by the model was in good agreement (around 5% difference) with measured temperature by a fiber optic probe, for three other MRI sequences., Conclusion: This method proposes a rapid and reliable quantification of the temperature rise near an implanted wire. Calibration data set and resulting fitting coefficients can be used to estimate temperature increase for any MRI sequence as function of its power and duration., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Marylene Delcey and Wadie Ben Hassen are employees of Siemens Healthcare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The Deep Underground Neutrino Experiment (DUNE) will be a powerful tool for a variety of physics topics. The high-intensity proton beams provide a large neutrino flux, sampled by a near detector system consisting of a combination of capable precision detectors, and by the massive far detector system located deep underground. This configuration sets up DUNE as a machine for discovery, as it enables opportunities not only to perform precision neutrino measurements that may uncover deviations from the present three-flavor mixing paradigm, but also to discover new particles and unveil new interactions and symmetries beyond those predicted in the Standard Model (SM). Of the many potential beyond the Standard Model (BSM) topics DUNE will probe, this paper presents a selection of studies quantifying DUNE's sensitivities to sterile neutrino mixing, heavy neutral leptons, non-standard interactions, CPT symmetry violation, Lorentz invariance violation, neutrino trident production, dark matter from both beam induced and cosmogenic sources, baryon number violation, and other new physics topics that complement those at high-energy colliders and significantly extend the present reach., (© The Author(s) 2021.)

Background: Transcranial focus ultrasound applications applied under MRI-guidance benefit from unrivaled monitoring capabilities, allowing the recording of real-time anatomical information and biomarkers like the temperature rise and/or displacement induced by the acoustic radiation force. Having both of these measurements could allow for better targeting of brain structures, with improved therapy monitoring and safety., Method: We investigated the use of a novel MRI-pulse sequence described previously in Bour et al., (2017) to quantify both the displacement and temperature changes under various ultrasound sonication conditions and in different regions of the brain. The method was evaluated in vivo in a non-human primate under anesthesia using a single-element transducer (f = 850 kHz) in a setting that could mimic clinical applications. Acquisition was performed at 3 T on a clinical imaging system using a modified single-shot gradient echo EPI sequence integrating a bipolar motion-sensitive encoding gradient. Four slices were acquired sequentially perpendicularly or axially to the direction of the ultrasound beam with a 1-Hz update frequency and an isotropic spatial resolution of 2-mm. A total of twenty-four acquisitions were performed in three different sets of experiments. Measurement uncertainty of the sequence was investigated under different acoustic power deposition and in different regions of the brain. Acoustic simulation and thermal modeling were performed and compared to experimental data., Results: The sequence simultaneously provides relevant information about the focal spot location and visualization of heating of brain structures: 1) The sequence localized the acoustic focus both along as well as perpendicular to the ultrasound direction. Tissue displacements ranged from 1 to 2 μm. 2) Thermal rise was only observed at the vicinity of the skull. Temperature increase ranged between 1 and 2 °C and was observed delayed relative the sonication due to thermal diffusion. 3) The fast frame rate imaging was able to highlight magnetic susceptibility artifacts related to breathing, for the most caudal slices. We demonstrated that respiratory triggering successfully restored the sensitivity of the method (from 0.7 μm to 0.2 μm). 4) These results were corroborated by acoustic simulations., Conclusions: The current rapid, multi-slice acquisition and real-time implementation of temperature and displacement visualization may be useful in clinical practices. It may help defining operational safety margins, improving therapy precision and efficacy. Simulations were in good agreement with experimental data and may thus be used prior treatment for procedure planning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Magnetic resonance (MR) thermometry allows visualization of lesion formation in real-time during cardiac radiofrequency (RF) ablation. The present study was performed to evaluate the precision of MR thermometry without RF heating in patients exhibiting cardiac arrhythmia in a clinical setting. The evaluation relied on quantification of changes in temperature measurements caused by noise and physiological motion., Methods: Fourteen patients referred for cardiovascular magnetic resonance imaging underwent an extra sequence to test the temperature mapping stability during free-breathing acquisition. Phase images were acquired using a multi-slice, cardiac-triggered, single-shot echo planar imaging sequence. Temperature maps were calculated and displayed in real-time while the electrocardiogram (ECG) was recorded. The precision of temperature measurement was assessed by measuring the temporal standard deviation and temporal mean of consecutive temperature maps over a period of three minutes. The cardiac cycle was analyzed from ECG recordings to quantify the impact of arrhythmia events on the precision of temperature measurement. Finally, two retrospective strategies were tested to remove acquisition dynamics related either to arrhythmia events or sudden breathing motion., Results: ECG synchronization allowed categorization of inter-beat intervals (RR) into distinct beat morphologies. Five patients were in stable sinus rhythm, while nine patients showed irregular RR intervals due to ectopic beats. An average temporal standard deviation of temperature of 1.6°C was observed in patients under sinus rhythm with a frame rate corresponding to the heart rate of the patient. The temporal standard deviation rose to 2.5°C in patients with arrhythmia. The retrospective rejection strategies increased the temperature precision measurement while maintaining a sufficient frame rate., Conclusions: Our results indicated that real-time cardiac MR thermometry shows good precision in patients under clinical conditions, even in the presence of arrhythmia. By providing real-time visualization of temperature distribution within the myocardium during RF delivery, MR thermometry could prevent insufficient or excessive heating and thus improve safety and efficacy., (© 2019 John Wiley & Sons, Ltd.)

The NOvA experiment has seen a 4.4σ signal of ν[over ¯]&#95;{e} appearance in a 2 GeV ν[over ¯]&#95;{μ} beam at a distance of 810 km. Using 12.33×10^{20} protons on target delivered to the Fermilab NuMI neutrino beamline, the experiment recorded 27 ν[over ¯]&#95;{μ}→ν[over ¯]&#95;{e} candidates with a background of 10.3 and 102 ν[over ¯]&#95;{μ}→ν[over ¯]&#95;{μ} candidates. This new antineutrino data are combined with neutrino data to measure the parameters |Δm&#95;{32}^{2}|=2.48&#95;{-0.06}^{+0.11}×10^{-3}  eV^{2}/c^{4} and sin^{2}θ&#95;{23} in the ranges from (0.53-0.60) and (0.45-0.48) in the normal neutrino mass hierarchy. The data exclude most values near δ&#95;{CP}=π/2 for the inverted mass hierarchy by more than 3σ and favor the normal neutrino mass hierarchy by 1.9σ and θ&#95;{23} values in the upper octant by 1.6σ.

Introduction: Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) treatments of mobile organs require locking the HIFU beam on the targeted tissue to maximise heating efficiency. We propose to use a standalone 3 D ultrasound (US)-based motion correction technique using the HIFU transducer in pulse-echo mode. Validation of the method was performed in vitro and in vivo in the liver of pig under MR-thermometry., Methods: 3 D-motion estimation was implemented using ultrasonic speckle-tracking between consecutive acquisitions. Displacement was estimated along four sub-apertures of the HIFU transducer by computing the normalised cross-correlation of backscattered signals followed by a triangulation algorithm. The HIFU beam was steered accordingly and energy was delivered under real-time MR-thermometry (using the proton resonance frequency shift method with online motion compensation and correction of associated susceptibility artefacts). An MR-navigator echo was used to assess the quality of the US-based motion correction., Results: Displacement estimations from US measurements were in good agreement with 1 D MR-navigator echo readings. In vitro, the maximum temperature increase was improved by 37% as compared to experiments performed without motion correction and temperature distribution remained much more focussed. Similar results were reported in vivo, with an increase of 35% on the maximum temperature using this US-based HIFU target locking., Conclusion: This standalone 3D US-based motion correction technique is robust and allows maintaining the HIFU focal spot in the presence of motion without adding any burden or complexity to MR thermal imaging. In vitro and in vivo results showed about 35% improvement in heating efficiency when focus position was locked on the target using the proposed technique.

Described here is a study of transesophageal thermal ablation of isolated and perfused beating hearts and non-human primates. An endoscope integrating a transesophageal echocardiography probe and a high-intensity focused ultrasound transducer was built and tested on five Langendorff-isolated hearts and three 30-kg baboons. B-Mode ultrasound, passive elastography and magnetic resonance imaging were performed to monitor thermal lesions. In isolated hearts, continuous and gated sonication parameters were evaluated with acoustic intensities of 9-12 W/cm 2 . Sonication parameters of gated exposures with 12 W/cm 2 acoustic intensity for 5 min consistently produced visible lesions in the ventricles of isolated hearts. In animals, left atria and ventricles were exposed to repeated continuous sonications (4-15 times for 16 s) at an acoustic intensity at the surface of the transducer of 9 W/cm 2 . Clinical states of the baboons during and after the treatment were good. One suspected lesion in the left ventricle could be evidenced by elastography, but was not confirmed by magnetic resonance imaging. The transesophageal procedure therefore has the potential to create thermal lesions in beating hearts and its safety in clinical practice seems promising. However, further technical exploration of the energy deposition in the target would be necessary before the next pre-clinical experiments., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Monitoring thermal therapies through medical imaging is essential in order to ensure that they are safe, efficient and reliable. In this paper, we propose a new approach, halfway between MR acoustic radiation force imaging (MR-ARFI) and MR elastography (MRE), allowing for the quantitative measurement of the elastic modulus of tissue in a highly localized manner. It relies on the simulation of the MR-ARFI profile, which depends on tissue biomechanical properties, and on the identification of tissue elasticity through the fitting of experimental displacement images measured using rapid MR-ARFI. This method was specifically developed to monitor MR-guided high intensity focused ultrasound (MRgHIFU) therapy. Elasticity changes were followed during HIFU ablations (N  =  6) performed ex vivo in porcine muscle samples, and were compared to temperature changes measured by MR-thermometry. Shear modulus was found to increase consistently and steadily a few seconds after the heating started, and such changes were found to be irreversible. The shear modulus was found to increase from 1.49  ±  0.48 kPa (before ablation) to 3.69  ±  0.93 kPa (after ablation and cooling). Thanks to its ability to perform quantitative elasticity measurements in a highly localized manner around the focal spot, this method proved to be particularly attractive for monitoring HIFU ablations.

The increase in nonradiative pathways with decreasing emission energy reduces the luminescence quantum yield (QY) of near-infrared photoluminescent (NIR PL) metal nanoclusters. Efficient surface ligand chemistry can significantly improve the luminescence QY of NIR PL metal nanoclusters. In contrast to the widely reported but modestly effective thiolate ligand-to-metal core charge transfer, we show that metal-to-ligand charge transfer (MLCT) can be used to greatly enhance the luminescence QY of NIR PL gold nanoclusters (AuNCs). We synthesized water-soluble and colloidally stable NIR PL AuNCs with unprecedentedly high QY (∼25%) upon introduction of triphenylphosphonium moieties into the surface capping layer. By using a combination of spectroscopic and theoretical methods, we provide evidence for gold core-to-ligand charge transfer occurring in AuNCs. We envision that this work can stimulate the development of these unusually bright AuNCs for promising optoelectronic, bioimaging, and other applications.

Purpose: The therapy endpoint most commonly used in MR-guided high intensity focused ultrasound is the thermal dose. Although namely correlated with nonviable tissue, it does not account for changes in mechanical properties of tissue during ablation. This study presents a new acquisition sequence for multislice, subsecond and simultaneous imaging of tissue temperature and displacement during ablation., Methods: A single-shot echo planar imaging sequence was implemented using a pair of motion-encoding gradients, with alternated polarities. A first ultrasound pulse was synchronized on the second lobe of the motion-encoding gradients and followed by continuous sonication to induce a local temperature increase in ex vivo muscle and in vivo on pig liver. Lastly, the method was evaluated in the brain of two volunteers to assess method's precision., Results: For thermal doses higher than the lethal threshold, displacement amplitude was reduced by 21% and 28% at the focal point in muscle and liver, respectively. Displacement value remained nearly constant for nonlethal thermal doses values. The mean standard deviation of temperature and displacement in the brain of volunteers remained below 0.8 °C and 2.5 µm., Conclusion: This new fast imaging sequence provides real-time measurement of temperature distribution and displacement at the focus during HIFU ablation. Magn Reson Med 78:1911-1921, 2017. © 2017 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

The use of magnetic resonance (MR) thermometry for the monitoring of thermal ablation is rapidly expanding. However, this technique remains challenging for the monitoring of the treatment of cardiac arrhythmia by radiofrequency ablation due to the heart displacement with respiration and contraction. Recent studies have addressed this problem by compensating in-plane motion in real-time with optical-flow based tracking technique. However, these algorithms are sensitive to local variation of signal intensity on magnitude images associated with tissue heating. In this study, an optical-flow algorithm was combined with a principal component analysis method to reduce the impact of such effects. The proposed method was integrated to a fully automatic cardiac MR thermometry pipeline, compatible with a future clinical workflow. It was evaluated on nine healthy volunteers under free breathing conditions, on a phantom and in vivo on the left ventricle of a sheep. The results showed that local intensity changes in magnitude images had lower impact on motion estimation with the proposed method. Using this strategy, the temperature mapping accuracy was significantly improved.

Purpose: A new real-time MR-thermometry pipeline was developed to measure multiple temperature images per heartbeat with 1.6×1.6×3 mm 3 spatial resolution. The method was evaluated on 10 healthy volunteers and during radiofrequency ablation (RFA) in sheep., Methods: Multislice, electrocardiogram-triggered, echo-planar imaging was combined with parallel imaging, under free breathing conditions. In-plane respiratory motion was corrected on magnitude images by an optical flow algorithm. Motion-related susceptibility artifacts were compensated on phase images by an algorithm based on Principal Component Analysis. Correction of phase drift and temporal filter were included in the pipeline implemented in the Gadgetron framework. Contact electrograms were recorded simultaneously with MR thermometry by an MR-compatible ablation catheter., Results: The temporal standard deviation of temperature in the left ventricle remained below 2 °C on each volunteer. In sheep, focal heated regions near the catheter tip were observed on temperature images (maximal temperature increase of 38 °C) during RFA, with contact electrograms of acceptable quality. Thermal lesion dimensions at gross pathology were in agreement with those observed on thermal dose images., Conclusion: This fully automated MR thermometry pipeline (five images/heartbeat) provides direct assessment of lesion formation in the heart during catheter-based RFA, which may improve treatment of cardiac arrhythmia by ablation. Magn Reson Med 77:673-683, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Background: Clinical treatment of cardiac arrhythmia by radiofrequency ablation (RFA) currently lacks quantitative and precise visualization of lesion formation in the myocardium during the procedure. This study aims at evaluating thermal dose (TD) imaging obtained from real-time magnetic resonance (MR) thermometry on the heart as a relevant indicator of the thermal lesion extent., Methods: MR temperature mapping based on the Proton Resonance Frequency Shift (PRFS) method was performed at 1.5 T on the heart, with 4 to 5 slices acquired per heartbeat. Respiratory motion was compensated using navigator-based slice tracking. Residual in-plane motion and related magnetic susceptibility artifacts were corrected online. The standard deviation of temperature was measured on healthy volunteers (N = 5) in both ventricles. On animals, the MR-compatible catheter was positioned and visualized in the left ventricle (LV) using a bSSFP pulse sequence with active catheter tracking. Twelve MR-guided RFA were performed on three sheep in vivo at various locations in left ventricle (LV). The dimensions of the thermal lesions measured on thermal dose images, on 3D T1-weighted (T1-w) images acquired immediately after the ablation and at gross pathology were correlated., Results: MR thermometry uncertainty was 1.5 °C on average over more than 96% of the pixels covering the left and right ventricles, on each volunteer. On animals, catheter repositioning in the LV with active slice tracking was successfully performed and each ablation could be monitored in real-time by MR thermometry and thermal dosimetry. Thermal lesion dimensions on TD maps were found to be highly correlated with those observed on post-ablation T1-w images (R = 0.87) that also correlated (R = 0.89) with measurements at gross pathology., Conclusions: Quantitative TD mapping from real-time rapid CMR thermometry during catheter-based RFA is feasible. It provides a direct assessment of the lesion extent in the myocardium with precision in the range of one millimeter. Real-time MR thermometry and thermal dosimetry may improve safety and efficacy of the RFA procedure by offering a reliable indicator of therapy outcome during the procedure.

Currently, no non-invasive cardiac pacing device acceptable for prolonged use in conscious patients exists. High Intensity Focused Ultrasound (HIFU) can be used to perform remote pacing using reversibility of electromechanical coupling of cardiomyocytes. Here we described an extracorporeal cardiac stimulation device and study its efficacy and safety. We conducted experiments ex vivo and in vivo in a large animal model (pig) to evaluate clinical potential of such a technique. The stimulation threshold was determined in 10 different ex vivo hearts and different clinically relevant electrical effects such as consecutive stimulations of different heart chambers with a single ultrasonic probe, continuous pacing or the inducibility of ventricular tachycardia were shown. Using ultrasonic contrast agent, consistent cardiac stimulation was achievable in vivo for up to 1 hour sessions in 4 different animals. No damage was observed in inversion-recovery MR sequences performed in vivo in the 4 animals. Histological analysis revealed no differences between stimulated and control regions, for all ex vivo and in vivo cases.

To provide a model close to the human heart, and to study intrinsic cardiac function at the same time as electromechanical coupling, we developed a magnetic resonance (MR)-compatible setup of isolated working perfused pig hearts. Hearts from pigs (40 kg, n = 20) and sheep (n = 1) were blood perfused ex vivo in the working mode with and without loaded right ventricle (RV), for 80 min. Cardiac function was assessed by measuring left intraventricular pressure and left ventricular (LV) ejection fraction (LVEF), aortic and mitral valve dynamics, and native T1 mapping with MR imaging (1.5 Tesla). Potential myocardial alterations were assessed at the end of ex vivo perfusion from late-Gadolinium enhancement T1 mapping. The ex vivo cardiac function was stable across the 80 min of perfusion. Aortic flow and LV-dP/dtmin were significantly higher (P < 0.05) in hearts perfused with loaded RV, without differences for heart rate, maximal and minimal LV pressure, LV-dP/dtmax, LVEF, and kinetics of aortic and mitral valves. T1 mapping analysis showed a spatially homogeneous distribution over the LV. Simultaneous recording of hemodynamics, LVEF, and local cardiac electrophysiological signals were then successfully performed at baseline and during electrical pacing protocols without inducing alteration of MR images. Finally, (31)P nuclear MR spectroscopy (9.4 T) was also performed in two pig hearts, showing phosphocreatine-to-ATP ratio in accordance with data previously reported in vivo. We demonstrate the feasibility to perfuse isolated pig hearts in the working mode, inside an MR environment, allowing simultaneous assessment of cardiac structure, mechanics, and electrophysiology, illustrating examples of potential applications., (Copyright © 2016 the American Physiological Society.)

Developing applications for metal-mediated base pairs (metallo-base-pair) has recently become a high-priority area in nucleic acid research, and physicochemical analyses are important for designing and fine-tuning molecular devices using metallo-base-pairs. In this study, we characterized the Hg(II)-mediated T-T (T-Hg(II)-T) base pair by Raman spectroscopy, which revealed the unique physical and chemical properties of Hg(II). A characteristic Raman marker band at 1586 cm(-1) was observed and assigned to the C4=O4 stretching mode. We confirmed the assignment by the isotopic shift ((18)O-labeling at O4) and density functional theory (DFT) calculations. The unusually low wavenumber of the C4=O4 stretching suggested that the bond order of the C4=O4 bond reduced from its canonical value. This reduction of the bond order can be explained if the enolate-like structure (N3=C4-O4(-)) is involved as a resonance contributor in the thymine ring of the T-Hg(II)-T pair. This resonance includes the N-Hg(II)-bonded state (Hg(II)-N3-C4=O4) and the N-Hg(II)-dissociated state (Hg(II+) N3=C4-O4(-)), and the latter contributor reduced the bond order of N-Hg(II). Consequently, the Hg(II) nucleus in the T-Hg(II)-T pair exhibited a cationic character. Natural bond orbital (NBO) analysis supports the interpretations of the Raman experiments.

The four-stranded G-quadruplex motif is a conformation frequently adopted by guanine-rich nucleic acids that plays an important role in biology, medicine, and nanotechnology. Although vibrational spectroscopy has been widely used to investigate nucleic acid structure, association of particular spectral features with the quadruplex structure has to date been ambiguous. In this work, experimental IR absorption and vibrational circular dichroism (VCD) spectra of the model quadruplex systems d(G)(8) and deoxyguanosine-5'-monophosphate (5'-dGMP) were analyzed using molecular dynamics (MD) and quantum-chemical modeling. The experimental spectra were unambiguously assigned to the quadruplex DNA arrangement, and several IR and VCD bands related to this structural motif were determined. Involvement of MD in the modeling was essential for realistic simulation of the spectra. The VCD signal was found to be more sensitive to dynamical structural variations than the IR signal. The combination of the spectroscopic techniques with multiscale simulations provides extended information about nucleic acid conformations and their dynamics.

The growing need for the characterization of cytochrome P450 (P450) metabolites often necessitates their synthesis up to Gram-scale. This task may in principle be achieved by using various techniques including chemical synthesis, the use of laboratory animals, in vitro P450 systems or microbial biotransformation. However, these approaches are in many instances unfavorable due to low yields, laborious purification, costs of cofactors, or the formation of non-physiologic metabolites. The fission yeast Schizosaccharomyces pombe has previously been shown by others and us to be very well suited for the heterologous expression of human P450s. In this study, we demonstrate whole-cell biotransformation reactions carried out with fission yeast strains that coexpress human cytochrome P450 reductase (CPR) and one of the following P450 isoforms: CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, respectively. These strains could successfully convert their respective standard substrates but showed different responses with respect to incubation pH, the presence of glucose, and temperature, respectively. In addition, the preparative of synthesis of 2.8 g of 4'-hydroxydiclofenac was achieved by whole-cell biotransformation of diclofenac using a CPR-CYP2C9 coexpressing fission yeast strain.

Reliable modeling of protein and peptide circular dichroism (CD) spectra in the far UV presents a challenge for current theoretical approaches. In this study, the time-dependent density functional theory (TDDFT), configuration interaction with single excitation (CIS), and transition dipole coupling (TDC) were used to assess the most important factors contributing to the CD spectra of the α-helical secondary structure. The dependence on the peptide chain length and also the role of the flexibility and solvent environment were investigated with a model oligopeptide Ac-(Ala)(N)-NH-Me, (N = 1, ..., 18). Both the TDDFT and TDC-like methods suggest that the CD curve typical for the α-helix arises gradually, but its basic characteristic is discernible already for peptides with 4-5 amino acid residues. The calculated dependence was in a qualitative agreement with experimental spectra of short α-helices stabilized by the histidine-metal binding. The TDDFT computations of the CD were found to be unusually sensitive to the basis set and solvent model. Explicit hydration and temperature fluctuations of the peptide geometry, simulated with the aid of molecular dynamics (MD), significantly influenced the CD and absorption spectral shapes. An extensive averaging over MD configurations is thus required to obtain a converged spectral profile in cluster simulations. On the other hand, both the TDDFT and TDC models indicate only a minor influence of the alanine side chains. The CIS and TDC calculations also point toward a relatively small effect of the helix-helix interaction on the CD spectral profiles. For a model system of two helices, the CIS method predicted larger changes in the spectra than TDC. This suggests other than interactions between peptide chains, such as mutual polarization, can have a minor, but measurable, effect on the CD spectrum.

The formation and structure of the potassium complex with valinomycin in solution were studied by means of Raman and Raman optical activity (ROA) spectroscopy. The complexation caused significant spectral changes, particularly in the region 1200-1400 cm(-1). The experimental spectra were interpreted using first principles computations. A complete computational conformational search combined with the spectral analysis revealed the arrangement of the isopropyl side chains in the complex. From a total of 6579 unique conformers two predominant ones were confirmed in the solution by ROA. A third one was predicted theoretically, but its population in the experiment could be estimated only roughly. The most populated conformer does not exhibit C(3) symmetry, and is different from that present in the crystal and the NMR-derived structure. Molecular dynamics techniques were used to estimate the molecular flexibility and its effect on the spectra. Density functional computations and Cartesian coordinate transfer (CCT) techniques provided the ROA and Raman spectral shapes and intensities well comparable with the experiment. The polar solvent (methanol) environment modeled with a polarizable continuum model (PCM) leads to rather minor changes in the conformer populations and vibrational properties as compared to vacuum computations, due to the hydrophobic character of the complex. Additional computational experiments suggest that the vibrational interactions determining the ROA spectra are quite local, which contributes to the good spatial resolution of the method. A reduction of the noise in the experimental spectra as well as increased precision of the simulations is desirable for the further exploration of the potential of the ROA spectroscopy for biomolecular studies in the future.

A fast and convenient spectroscopic methodology to determine the water uptake capacity of amphiphile assemblies studied in multilayer films is presented. This method was developed to provide a reliable but relatively simple tool for estimating the binding potency of such complex systems. The water-binding potency represents a general propensity of higher-order systems to bind or embed relevant ligands, such as various non-lipid effectors in the case of artificial lipid membranes. In this sense, the binding potency might contribute to a specific functional role of certain lipids. The essence of the new method is that the calibration of data measured by infrared (IR) spectroscopy against those directly obtained by Karl-Fischer titration (KFT) enables one to replace the expensive chemical-analytical technique by a more comfortable and efficient IR-spectroscopic protocol. This approach combines the easy handling, versatility, and availability of IR spectroscopy with the high accuracy of KFT. The usefulness of the procedure is demonstrated on an example set of six amphiphiles with a common chain length of 18 carbon atoms. Despite this similarity, the binding potency data differ tremendously in a way which can be correlated with the systematic variations introduced into the amphiphile structure. Going further beyond the methodical aspect, the scientific relevance of the data is comprehensively discussed especially in terms of the structural factors that govern the binding potency of amphiphiles. That is favored mainly by fluidity and disfavored mainly by inter-amphiphile binding networks. For phosphatidylcholine, our data are strongly in favor of a particular hydration model that involves primary water binding to phosphate as well as the formation of water semi-clathrates hosting the trimethylammonium moiety. Interestingly, stearylamine and diolein assemblies did not take up any water at all. This unexpected hydrophobicity is due to the unusual structures formed in these latter cases: rigid ammonium amide with a strong hydrogen-bonding/salt bridge network in stearylamine, and patches of inverted micelles in diolein, as revealed by molecular dynamics simulations.

Experimental and theoretical specific optical rotations (OR) of anhydro, epithio, and epiminoderivatives of methyl tetrofuranosides in chloroform solutions have been compared and used as a tool for exploring their conformational behavior. The potential energy surfaces of these saccharides with reduced flexibility were examined with the density functional theory and the MP2 and CCSD(T) wavefunctions methods. Theoretical ORs were obtained by Boltzmann averaging of values calculated for local minima. Resultant rotations could be used to assess the quality of the DFT and MP2 relative conformer energies. OR values calculated for equilibrium geometries in vacuum were significantly improved when the solvent was accounted for by a polarizable continuum model and first and diagonal second OR derivatives were used for an anharmonic vibrational averaging. The DFT used as a default method reproduced the experimental data fairly well. A modified B3LYP functional containing 70% of HF exchange further improved the results. Because of the strong dependence of OR on the conformation, not only the absolute configuration could be determined, but also the conformational populations were estimated. Likewise, the predicted dependence of OR on the light wavelength well agreed with experiment. The increasing precision of the contemporary computational methods thus makes it possible to relate the specific rotation to more detailed features in molecular structure., ((c) 2010 Wiley Periodicals, Inc.)

Accurate simulations of vibrational molecular spectra require precise molecular force fields, at least with cubic and quartic anharmonic corrections beyond the harmonic limits. Generation of such force field terms becomes computationally prohibitive for larger molecules. In this work, an alternate possibility is explored, where approximate anharmonic force field components are obtained from molecular fragments. Transferability properties of the cubic and incomplete quartic fields are discussed and tested on model oligoproline molecules. Automatic transfer schemes including cubic, two and three atomic quartic force constants are developed and implemented. The results indicate that the main vibrational interactions in molecules are local and the anharmonic constants are mostly well amendable to the transfer. Exact anharmonic normal mode force fields of larger molecules compared very well to those obtained from smaller molecular parts. The most important changes in vibrational spectra caused by the anharmonic interactions could be reproduced with two and three atomic force field terms. The transfer scheme thus provides molecular anharmonic force fields without a significant loss of accuracy and brings significant savings of computer time and memory needed to generate molecular vibrational energies and spectra.

A model peptide, cyclo-(Phe-d-Pro-Gly-Arg-Gly-Asp), with a distinct folded structure containing short beta-hairpin and beta-sheet patterns was studied by Raman and Raman optical activity (ROA) spectroscopies. Unlike for previously analyzed vibrational circular dichroism of the same compound (Chirality 2008, 20, 1104), the Raman spectrum is dominated by side chain contributions and is more sensitive to their geometry fluctuations. The spectra and molecular motion were analyzed with the aid of the density functional theory simulations combined with molecular dynamics (MD). The side chain geometry fluctuations were found to significantly contribute to the broadening of the spectral bands, while dynamics of the backbone is rather restricted. According to our MD results, the side chains do not move freely but largely oscillate around preferred conformations. Averaging of computed spectra for many structures derived from the MD trajectories provided better spectral profiles than did a fixed geometry. The Raman and ROA scattering is dominated by the more polarizable phenylalanine and proline groups, as could be verified both by the computations and by comparison to experiments with a model Phe-d-Pro dipeptide. Computational analyses suggest that the ROA spectrum mostly senses local side chain conformation, whereas a vibrational coupling between different side chains contributes less. The coupling is mostly mediated by the peptide backbone and is restricted to specific vibrational region. The ROA spectroscopic technique thus provides important local structural information that needs, however, to be extracted by multiscale (QM/MM) simulation techniques.

Using dihydrogendisulphide (H(2)S(2)), dimethyl- ((CH(3))(2)S(2)), and diethyldisulphide ((CH(3)CH(2))(2)S(2))as model molecules, theoretical ECD, VCD, and ROA spectra of nonplanar disulphides were calculated by DFT methods. Most of the calculated electronic and vibrational chiroptical features suffer an equivocal relation between calculatedsigns of ECD, VCD, or ROA and the sense of disulphide nonplanarity as noted earlier for low-lying ECD bands. This is a consequence of local C(2) symmetry of a disulphide group causing most electronic and vibrational transitions to occur as pairs falling to alternative A, B symmetry species, which become degenerate and switch their succession (and consequently the observed chiroptical sign pattern) at the energetically most favorable perpendicular conformation. According to present calculations, the key to resolving this ambiguity may involve the S-S stretching vibrational mode at approximately 500 cm(-1). The relation of signs of the relevant VCD and ROA features to sense of disulphide chirality seems simpler and less ambiguous. The right-handed arrangement of the S-S group (0 < chi(S-S) < 180 degrees) results in mostly negative VCD signals. Although relation to ROA still suffers some ambiguity, it gets clearer along the series H(2)S(2)-(CH(3))(2)S(2)-(CH(3)CH(2))(2)S(2). ROA is also attractive for the analysis of disulphide-containing peptides and proteins, because applying it to aqueous solutions is not problematic., (Copyright 2009 Wiley-Liss, Inc.)

Hydration envelopes of metallic ions significantly influence their chemical properties and biological functioning. Previous computational studies, nuclear magnetic resonance (NMR), and vibrational spectra indicated a strong affinity of the Mg(2+) cation to water. We find it interesting that, although monatomic ions do not vibrate themselves, they cause notable changes in the water Raman signal. Therefore, in this study, we used a combination of Raman spectroscopy and computer modeling to analyze the magnesium hydration shell and origin of the signal. In the measured spectra of several salts (LiCl, NaCl, KCl, MgCl(2), CaCl(2), MgBr(2), and MgI(2) water solutions), only the spectroscopic imprint of the hydrated Mg(2+) cation could clearly be identified as an exceptionally distinct peak at approximately 355 cm(-1). The assignment of this band to the Mg-O stretching motion could be confirmed on the basis of several models involving quantum chemical computations on metal/water clusters. Minor Raman spectral features could also be explained. Ab initio and Fourier transform (FT) techniques coupled with the Car-Parrinello molecular dynamics were adapted to provide the spectra from dynamical trajectories. The results suggest that even in concentrated solutions magnesium preferentially forms a [Mg(H(2)O)(6)](2+) complex of a nearly octahedral symmetry; nevertheless, the Raman signal is primarily associated with the relatively strong metal-H(2)O bond. Partially covalent character of the Mg-O bond was confirmed by a natural bond orbital analysis. Computations on hydrated chlorine anion did not provide a specific signal. The FT techniques gave good spectral profiles in the high-frequency region, whereas the lowest-wavenumber vibrations were better reproduced by the cluster models. Both dynamical and cluster computational models provided a useful link between spectral shapes and specific ion-water interactions.

Calix[4]phyrins are convenient models for porphyrin metabolism intermediates. They also attract attention as complexation agents in macromolecular chemistry. For the biological function and chemical properties, their flexibility plays an important role. In this study, we explore the inner hydrogen motion previously detected in some calix[4]phyrins as a slow chemical exchange in the NMR spectra (J. Am. Chem. Soc. 2004, 126, 13714). The potential energy surface of this motion is defined by two generalized coordinates and modeled at DFT levels. The transitional barriers thus obtained agree reasonably well with those calculated from dynamic (1)H NMR measurements. The transitions over both the sp(2) and sp(3) links are found to be possible. During the transfer, an intermediate is formed where the two hydrogen atoms are attached to the neighboring nitrogens. Surprisingly, the barriers channeling the sp(2) and sp(3) paths in significantly depend on the dispersion and other interactions between remote side chains. The results confirm the possibility of a fine-tuning of the calixphyrin core properties by distant substituents.

Skeletal rearrangement of a series of substituted Dewar benzenes to biaryl products was studied with DFT methods. Excellent agreement of calculated free energies of activation with experimental kinetic data was achieved. Two different transition states were proposed to be involved in the rearrangement. The reaction path was studied both by static intrinsic reaction coordinate (IRC) calculations and first-principles Car-Parrinello and Born-Oppenheimer molecular dynamics. All approaches confirmed the suggested reaction mechanism.

The structure of the alanine hydration shell was modeled by Carr-Parinello molecular dynamics (CPMD) to explain subtle differences in NMR chemical shifts and indirect spin-spin coupling constants of the neutral (zwitterionic), cationic, and anionic forms of this amino acid. In comparison with classical molecular dynamics (MD), the quantum mechanical CPMD approach revealed a more structured solvent and significant differences in the radial and angular distributions of the water molecules around the solute. In particular, the solvent was predicted to be organized around the uncharged COOH and NH(2) residues to a similar degree as that for the charged ones. This was not the case with MD. For snapshot CPMD configurations, the NMR parameters were computed by density functional theory (DFT) and averaged. Obtained values were significantly closer to experimental parameters known for (15)N and (13)C isotopically labeled alanine than those calculated by the conventional implicit dielectric solvent model. The NMR results also quantitatively reflect a superiority of the CPMD over the MD explicit solvent treatment. A further improvement of the computed spin-spin coupling constants could be achieved by taking into account vibrational averaging beyond the harmonic approximation. Differently positioned water molecules in the clusters cause an unexpectedly large scattering of the NMR parameters. About 10-15 dynamics snapshots were required for a satisfactory convergence of the shifts and couplings. The NMR chemical shift was found to be much more sensitive to the molecular hydration than the coupling. The results thus indicate a large potential of the NMR spectroscopy and quantum simulations to probe not only the structure of molecules but also their interactions with the environment.

The N-methylacetamide molecule (NMA) is an important model for peptide and protein vibrational spectroscopy as it contains the main amide chromophore. In the past, some observed NMA geometry and spectral features could not be entirely explained at the harmonic level or by a single-conformer model. In particular, the spectra were found to be very dependent on molecular environment. In this work NMA Raman and infrared (IR) spectra in a variety of conditions were remeasured and simulated theoretically to separate the fundamental, dimer, and anharmonic bands. Under vacuum the MP2, MP4, and CCSD(T) wave function methods predicted a broad anharmonic potential energy well or even a double-well for the amide nitrogen out of plane motion, which density functional methods failed to reproduce. However, eventual nonplanar minima cannot support an asymmetric quantum state or explain band splittings observed in some experiments. In polar solvents the potential becomes more harmonic and the amide plane more rigid. On the other hand, solvent polarity enhances other anharmonic phenomena, such as the coupling between the carbonyl stretching (amide I) and lower frequency amide bending modes. The amide I band splitting is commonly observed experimentally. The influence of the CH(3) group rotations modeled by a rigid rotor model was found to be important for explaining some features of the spectra in a solid parahydrogen matrix. At room temperature the methyl rotation contributes to a nonspecific inhomogeneous band broadening. The dependence of the amide group flexibility on the environment polarity may have interesting consequences for peptide and protein folding studies.

Fine effects of the hydration, charge, and conformational structural changes in L-alanyl-L-alanine (Ala-Ala) dipeptide were studied with the aid of Raman and Raman optical activity (ROA) spectra. The spectra were recorded experimentally and analyzed by means of density functional computations. A (15)N and (13)C isotopically labeled analogue was synthesized and used to verify the vibrational mode assignment. Calculated shifts in vibrational frequencies for isotopically labeled molecule agreed well with the experiment. The assignment made it possible to scale computed vibrational frequencies and extract better structural information from the intensities. Solvent modeling with clusters obtained from molecular dynamics led to a qualitatively correct inhomogeneous broadening of Raman spectral lines but did not bring a convincing improvement of ROA signal when compared to a standard dielectric solvent correction. In comparison with the zwitterionic form, charged anionic and cationic dipeptides provided spectral variations that indicated different conformational behavior. Only minor backbone conformational change occurs in the cation, whereas the results indicate the presence of more anion conformers differing in the rotation of the NH(2) group and the backbone psi-angle. These findings are in agreement with previous electronic circular dichroism (ECD) and NMR studies. The results confirm the large potential of the ROA technique for the determination of final details in molecular structure and conformation.

The information about molecular structure coded in the optical spectra must often be deciphered by complicated computational procedures. A combination of spectral modeling with the molecular dynamic simulations makes the process simpler, by implicit accounting for the inhomogeneous band broadening and Boltzmann averaging of many conformations. Ideally, geometries of studied systems can be deduced by a direct confrontation of such modeling with the experiment. In this work, the comparison is enhanced by restrictions to molecular dynamics propagations based on the Raman and Raman optical activity spectra. The methodology is introduced and tested on model systems comprising idealized H(2)O(2), H(2)O(3) molecules, and the alanine zwitterion. An additional gradient term based on the spectral overlap smoothed by Fourier transformation is constructed and added to the molecular energy during the molecular dynamics run. For systems with one prevalent conformation the method did allow to enrich the Boltzmann ensemble by a spectroscopically favored structure. For systems with multiconformational equilibria families preferential conformations can be selected. An alternative algorithm based on the comparison of the averaged spectra with the reference enabling iterative updates of the conformer probabilities provided even more distinct distributions in shorter times. It also accounts for multiconformer equilibria and provided realistic spectra and conformer distribution for the alanine., ((c) 2008 Wiley Periodicals, Inc.)

Conformational properties of a 12-residue tryptophan zipper (trpzip) beta-hairpin peptide (AWAWENGKWAWK-NH(2), a modification of the original trpzip2 sequence) are analyzed under equilibrium conditions using ECD and IR spectra of a series of variants, singly and doubly C(1)-labeled with (13)C on the amide CO. The characteristic features of the (13)CO component of the amide I' IR band and their sensitivity to the local structure of the peptide are used to differentiate stabilities for parts of the hairpin structure. Doubly labeled peptide spectra indicate that the ends of the beta-strands are frayed and that the center part is more stable as would be expected from formation of a stable hydrophobic core consisting of four tryptophan residues, and supported by MD simulations. NMR analyses were used to determine a best fit solution structure that is in close agreement with that of trpzip2, except for a small variation in the turn geometry. The distinct vibrational coupling patterns of the labeled sites based on this structure are also well matched by ab initio DFT-level calculations of their IR spectral patterns. Thermal unfolding of the peptides as studied with CD spectra could be fit with an apparent two-state transition model. ECD senses only the tryptophan interactions (tertiary-like) and their overall environment, as shown by TD-DFT modeling of the Trp-Trp pi-pi ECD. However, variation of the amide I IR spectra of (13)C-isotopomers showed that the thermal unfolding process is not cooperative in terms of the peptide backbone (secondary structure), since the transition temperatures sensed for labeled modes differ from those for the whole peptide. The thermal data also evidence dependence on concentration and pH but these cause little spectral variation. This study illustrates the consequences of multistate conformational change at the residue- or sequence-specific level in a system whose structure is dominated by hydrophobic collapse.

Raman scattering and its polarized extension, Raman optical activity (ROA), are commonly used for monitoring of molecular conformational equilibria in solutions. This is complicated for saccharides due to extensive motions of the hydroxyl groups and other molecular parts. Standard interpretation procedures involving ab initio spectral simulations for a limited set of conformers are not adequate. In this study, a more general approach is proposed for the gluconic acid anion taken as a model compound, where quantum simulations of the spectra are directly coupled with molecular dynamics (MD) techniques. Such a multiscale approach reveals how the structural information is encoded in the broadened spectral lines. The spectra were simulated for solvent-solute clusters generated by MD. Conformational averaging was enabled by a limited library of conformers for which the spectral parameters could be calculated ab initio and moved on the MD geometries by Cartesian coordinate tensor transfer techniques. The B3LYP/CPCM/6-31+G** approximation was used as a default for computation of the source force fields and polarizability derivatives. The spectra thus obtained relatively faithfully reproduced most of the experimental features. The Amber and polarizable Amoeba MD force fields produced similar results; application of the latter, however, was limited by the long time necessary to achieve a converged conformational equilibrium. Both MD simulation and spectral averaging suggest that the hydroxyl groups as well as the backbone C-C bonds rotate relatively freely, with some restrictions in the vicinity of the carboxyl group. In spite of the averaging, spectral response of characteristic vibrational normal mode families, such as CH and OH bending, can clearly be identified in the spectra. The simulations thus confirm the experimental fact that flexible saccharides exhibit significant vibrational activity that reveals precious information about molecular structure and dynamics encoded in the Raman and ROA spectral shapes.

The dependence of the effective chemical shielding anisotropy (effective CSA, Deltasigma(eff)) on the phi and psi peptide backbone torsion angles was calculated in the l-alanyl-l-alanine (LALA) peptide using the DFT method. The effects of backbone conformation, molecular charge including the cation, zwitterion, and anion forms of the LALA peptide, and the scaling taking into account the length of the dipolar vector were calculated for the effective CSAs in order to assess their structural behaviors and to predict their magnitudes which can be probed for the beta-sheet and alpha-helix backbone conformations via measurement of the cross-correlated relaxation rates (CCR rates). Twenty different CSA-DD cross-correlation mechanisms involving the amide nitrogen and carbonyl carbon chemical shielding tensors and the C(alpha)H(alpha) (alpha-carbon group), NH(N) (amide group), C(alpha)H(N), NH(alpha), C'H(alpha), and C'H(N) (alpha = alpha1, alpha2) dipolar vectors were investigated. The X-C(alpha)H(alpha) (X = N, C'; alpha = alpha1, alpha2) cross-correlations, which had already been studied experimentally, exhibited overall best performance of the calculated effective CSAs in the LALA molecule; they spanned the largest range of values upon variation of the psi and phi torsions and depended dominantly on only one of the two backbone torsion angles. The X-NH(N) (X = N, C') cross-correlations, which had been also probed experimentally, depended on both backbone torsions, which makes their structural assignment more difficult. The N-NH(alpha2) and N-C'H(alpha1) cross-correlations were found to be promising for the determination of various backbone conformations due to the large calculated range of the scaled effective CSA values and due to their predominant dependence on the psi and phi torsions, respectively. The 20 calculated dependencies of effective CSAs on the two backbone torsion angles can facilitate the structural interpretation of CCR rates.

Relative importance of anharmonic corrections to molecular vibrational energies, nuclear magnetic resonance (NMR) chemical shifts, and J-coupling constants was assessed for a model set of methane derivatives, differently charged alanine forms, and sugar models. Molecular quartic force fields and NMR parameter derivatives were obtained quantum mechanically by a numerical differentiation. In most cases the harmonic vibrational function combined with the property second derivatives provided the largest correction of the equilibrium values, while anharmonic corrections (third and fourth energy derivatives) were found less important. The most computationally expensive off-diagonal quartic energy derivatives involving four different coordinates provided a negligible contribution. The vibrational corrections of NMR shifts were small and yielded a convincing improvement only for very accurate wave function calculations. For the indirect spin-spin coupling constants the averaging significantly improved already the equilibrium values obtained at the density functional theory level. Both first and complete second shielding derivatives were found important for the shift corrections, while for the J-coupling constants the vibrational parts were dominated by the diagonal second derivatives. The vibrational corrections were also applied to some isotopic effects, where the corrected values reasonably well reproduced the experiment, but only if a full second-order expansion of the NMR parameters was included. Contributions of individual vibrational modes for the averaging are discussed. Similar behavior was found for the methane derivatives, and for the larger and polar molecules. The vibrational averaging thus facilitates interpretation of previous experimental results and suggests that it can make future molecular structural studies more reliable. Because of the lengthy numerical differentiation required to compute the NMR parameter derivatives their analytical implementation in future quantum chemistry packages is desirable.

Metal ion interactions with nucleic acids attract attention because of the environmental and biological consequences. The formation of the complex is often monitored by the vibrational spectroscopy. To identify characteristic binding patterns and marker bands on a model DNA component, infrared absorption spectra of the deoxyguanosine monophosphate complexes with Na(+), Mg(2+), Ca(2+), Ni(2+), Cu(2+), Zn(2+), and Cd(2+) cations were recorded and interpreted on the basis of density-functional computations. The aqueous environment was simulated by continuum and combined continuum-explicit solvent models. For the binding to the N7 position of the guanine base, the computation predicted a characteristic frequency upshift and splitting of the 1578 cm(-1) band, which is in accord with available experimental data. Contrary to the expectation, the modeling suggests that the binding to the carbonyl group might not be detectable, as the metal causes smaller spectral changes if compared to the hydrogen-bound water molecules. The binding to the phosphate group causes significant spectral changes in the sugar-phosphate vibrating region ( approximately 800-1200 cm(-1)), but also notable frequency shifts of the carbonyl vibrations. The Cu(2+) and Zn(2+) ions induced the largest alterations in observed vibrational absorption, which corresponds to the calculated strong interaction energies in the N7-complexes and to previous experimental experience. Additional changes in the vibrational spectra of the copper complexes were observed under high metal concentration, corresponding to the simultaneous binding to the phosphate residue. The two-step Cu(2+) binding process was also confirmed by the microcalorimetry titration curve. The computations and combination of more techniques thus help us to assign and localize spectral changes caused by the metal ion binding to nucleic acids.

In this work, time dependent density functional theory (TD-DFT) is used to provide a reliable basis for interpretation of the electronic spectra of coupled tryptophan (Trp) residues, particularly those in a model Trpzip beta-hairpin peptide. Pairs of isolated indoles form chiral coupled chromophores whose computed electronic ultraviolet circular dichroism (CD) is in excellent agreement with observed transition wavelengths and intensities. The calculations were compared to experimental data for pairwise coupling in mutant Trpzip peptides that are recently available. A study of variation of the basis set, geometry optimization, and the solvent environment on the spectra showed limited impact on bandshapes. An alternative simplified computational scheme, dependent on the transition dipole coupling (TDC) mechanism, is shown to give a representation of qualitative aspects of the intense CD for the (1)B bands at 228 and 213 nm. The results confirm the origin of the Trpzip diagnostic CD as primarily a dipolar interaction between Trp sidechains, and show that quantum computations of electronic CD can provide a reliable basis for interpretation of these chirally coupled aromatic spectral phenomena., ((c) 2009 Wiley-Liss, Inc.)

The samples used for the first observations of vibrational Raman optical activity (ROA) in 1972, namely both enantiomers of 1-phenylethanol and 1-phenylethylamine, have been revisited using a modern commercial ROA instrument together with state-of-the-art ab initio calculations. The simulated ROA spectra reveal for the first time the vibrational origins of the first reported ROA signals, which comprised similar couplets in the alcohol and amine in the spectral range approximately 280-400 cm(-1). The results demonstrate how easy and routine ROA measurements have become, and how current ab initio quantum-chemical calculations are capable of simulating experimental ROA spectra quite closely provided sufficient averaging over accessible conformations is included. Assignment of absolute configuration is, inter alia, completely secure from results of this quality. Anharmonic corrections provided small improvements in the simulated Raman and ROA spectra. The importance of conformational averaging emphasized by this and previous related work provides the underlying theoretical background to ROA studies of dynamic aspects of chiral molecular and biomolecular structure and behavior., ((c) 2009 Wiley-Liss, Inc.)

An increased circular dichroism (CD) signal of large molecular aggregates formed upon DNA condensation was observed a long time ago, and is often referred to as psi-CD. The effort to understand this phenomenon is further motivated by the latest DNA packing studies and advances in macromolecular chemistry. In the present work, the transition dipole coupling model describing interactions of molecules with light has been extended to handle systems of arbitrary size. The analytical formulae obtained retain the simplicity and computational speed of the standard approach. The origin of the psi-effect was investigated on several model systems. The results suggest that the CD enhancement is primarily caused by delocalized phonon-like excitations in nucleic acid strands. The size of the system exhibiting the effect thus does not need to be comparable with or greater than the wavelength of the absorbed light. Small structural irregularities still allow for the enhancement while a larger disorder breaks it. The modeling is consistent with previous experimental electronic and vibrational CD studies, and makes it possible to correlate the enhancement with the geometry of the nucleic acid systems., (2008 Wiley Periodicals, Inc.)

A model cyclohexapeptide, cyclo-(Phe-(D)Pro-Gly-Arg-Gly-Asp) was synthesized and its IR and VCD spectra were used as a test of density functional theory (DFT) level predictions of spectral intensities for a peptide with a nonrepeating but partially constricted conformation. Peptide structure and flexibility was estimated by molecular dynamics (MD) simulations and the spectra were simulated using full quantum mechanical (QM) approaches for the complete peptide and for simplified models with truncated side chains. After simulated annealing, the backbone conformation of the ring structure is relatively stable, consisting of a normal beta-turn and a tight loop (no H-bond) which does not vary over short trajectories. Only in quite long MD runs at high temperatures do other conformations appear. MD simulations were carried out for the cyclic peptide in water and in TFE, which match experimental solvents, as well as with and without protonation of the Asp carboxyl group. DFT spectral simulations were made using the annealed structure and were extended to include basis set variation, to determine an optimal computational approach, and solvent simulation with a polarized continuum model (PCM). Stepwise full DFT simulation of spectra was done for various sequences with the same backbone geometry but based on (1) solely Gly residues, (2) Ala substitution except Gly and Pro, and (3) complete sequences with side chains. Additionally, a selection of structures was used to compute IR and VCD spectra with the optimal method to determine structural variation effects. The side chains, especially the Asp-COOH and Arg-NH(2) transitions, had an impact on the computed amide frequencies, IR intensities and VCD pattern. Since experimentally these groups would have little chirality, due to conformational variation, they do not impact the observed VCD spectra. Correcting for frequency shifts, the Ala model for the cyclopeptide gives the clearest representation of the amide VCD. The experimental sign pattern for the amide I' band in D(2)O and also the sharper, more intense amide I VCD band in TFE was seen to some degree in one conformer with Type II' turns, but the data favor a mix of structures., (2008 Wiley-Liss, Inc.)

Interpretation of the Raman optical activity (ROA) of peptides is difficult because of molecular flexibility and interaction with the solvent. Typically, simulations and experiments are compared in terms of a qualitative agreement between the spectra. However, on a series of the Pro-Gly, Gly-Pro, Pro-Ala, and Ala-Pro dipeptides more precise conformer ratios could be obtained with the aid of the density functional computations and numerical decomposition of the spectral shapes. All observed transitions were assigned, and the computed transition frequencies were scaled accordingly. Then the populations predicted by the optical spectroscopy agreed within a few percent with an analysis of the spin-spin coupling constants based on the Karplus equations, which was confirmed also by a comparison of calculated and experimental NMR couplings. The results are supported by molecular dynamics simulations and related to the previous conformational studies of similar molecules.