Multimillion Atom Simulations of Di-8-ANEPPS Chromophores Embedded in a Model Plasma Membrane: Toward the Investigation of Realistic Dyed Cell Membranes.

A multistep computational approach has been employed to study a multimillion all-atom dyed plasma membrane, with no less than 42 different lipid species spanning the major head groups and a variety of fatty acids, as well as cholesterol, with the objective of investigating its structure and dynamics, as well as its impact on the embedded di-8-ANEPPS dyes. The latter are commonly used as bioimaging probes and serve as local microscopes. So, they provide information on membrane morphology via their second harmonic nonlinear optical (NLO) responses, which have the advantage of being specific to interface regions and sensitive to the chromophore environment. In previous studies, this chromophore has only been studied in simpler membrane models, far from the complexity of real lipid bilayers, while, owing to the ever-increasing computational resources, multimillion lipid bilayers have been studied, giving access to the effects of its heterogeneity. First, using molecular dynamics (MD) simulations, it is found that the combination of lipids produces a more ordered and denser membrane compared to its homogeneous model counterparts, while the local environment of the embedded dyes becomes enriched in phosphatidylcholine. Subsequently, the second harmonic first hyperpolarizability of the probes was calculated at the TDDFT level on selected frames of MD, highlighting the influence of the lipid environment. Due to the complexity of the system, machine learning (ML) tools have been employed to establish relationships between the membrane structural parameters, the orientation of the probes, and their NLO responses. These ML approaches have revealed influential features, including the presence of diacylglycerol lipids close to the dye. On the whole, this work provides a first step toward understanding the cooperation, synergy, and interactions that occur in such complex guest-host environments, which have emerged as new targets for drug design and membrane lipid therapy.

First hyperpolarizability of the di-8-ANEPPS and DR1 nonlinear optical chromophores in solution. An experimental and multi-scale theoretical chemistry study.

The solvent effects on the linear and second-order nonlinear optical properties of an aminonaphtylethenylpyridinium (ANEP) dye are investigated by combining experimental and theoretical chemistry methods. On the one hand, deep near infrared (NIR) hyper-Rayleigh scattering (HRS) measurements (1840-1950 nm) are performed on solutions of di-8-ANEPPS in deuterated chloroform, dimethylformamide, and dimethylsulfoxide to determine their first hyperpolarizablity (ßHRS). For the first time, these HRS experiments are carried out in the picosecond regime in the deep NIR with very moderate (≤3 mW) average input power, providing a good signal-to-noise ratio and avoiding solvent thermal effects. Moreover, the frequency dispersion of ßHRS is investigated for Disperse Red 1 (DR1), a dye commonly used as HRS external reference. On the other hand, these are compared with computational chemistry results obtained by using a sequential molecular dynamics (MD) then quantum mechanics (QM) approach. The MD method allows accounting for the dynamical nature of the molecular structures. Then, the QM part is based on TDDFT/M06-2X/6-311+G* calculations using solvation models ranging from continuum to discrete ones. Measurements report a decrease of the ßHRS of di-8-ANEPPS in more polar solvents and these effects are reproduced by the different solvation models. For di-8-ANEPPS and DR1, comparisons show that the use of a hybrid solvation model, combining the description of the solvent molecules around the probe by point charges with a continuum model, already achieves quasi quantitative agreement with experiment. These results are further improved by using a polarizable embedding that includes the atomic polarizabilities in the solvent description.

A quantum chemical investigation of the second hyperpolarizability of p-nitroaniline.

Recent measurements of the third harmonic scattering responses of molecules have given a new impetus for computing molecular second hyperpolarizabilities (γ) and for deducing structure-property relationships. This paper has employed a variety of wavefunction and density functional theory methods to evaluate the second hyperpolarizability of the p-nitroaniline prototypical push-pull π-conjugated molecule, addressing also numerical aspects, such as the selection of an integration grid and the impact of the order of differentiation vs the achievable accuracy by using the Romberg quadrature. The reliability of the different methods has been assessed by comparison to reference Coupled-Cluster Singles and Doubles with perturbative treatment of the Triples results. On the one hand, among wavefunction methods, the MP2 scheme offers the best accuracy/cost ratio for computing the static γ. On the other hand, using density functional theory, γ remains a challenging property to compute because all conventional, global hybrid or range-separated hybrid, exchange-correlation functionals underestimate static γ values by at least 15%. Even tuning the range-separating parameter to minimize the delocalization errors does not enable to improve the γ values. Nevertheless, the original double-hybrid B2-PLYP functional, which benefits from 27% of PT2 correlation and 53% Hartree-Fock exchange, provides accurate estimates of static γ values. Unfortunately, the best performing exchange-correlation functionals for γ are not necessarily reliable for the first hyperpolarizability, ß, and vice versa. In fact, the ß of p-nitroaniline (pNA) could be predicted, with a good accuracy, with several hybrid exchange-correlation functionals (including by tuning the range-separating parameter), but these systematically underestimate γ. As for γ, the MP2 wavefunction method remains the best compromise to evaluate the first hyperpolarizability of pNA at low computational cost.

HPC+ in the medical field: Overview and current examples.

BACKGROUND: To say data is revolutionising the medical sector would be a vast understatement. The amount of medical data available today is unprecedented and has the potential to enable to date unseen forms of healthcare. To process this huge amount of data, an equally huge amount of computing power is required, which cannot be provided by regular desktop computers. These areas can be (and already are) supported by High-Performance-Computing (HPC), High-Performance Data Analytics (HPDA), and AI (together "HPC+"). OBJECTIVE: This overview article aims to show state-of-the-art examples of studies supported by the National Competence Centres (NCCs) in HPC+ within the EuroCC project, employing HPC, HPDA and AI for medical applications. METHOD: The included studies on different applications of HPC in the medical sector were sourced from the National Competence Centres in HPC and compiled into an overview article. Methods include the application of HPC+ for medical image processing, high-performance medical and pharmaceutical data analytics, an application for pediatric dosimetry, and a cloud-based HPC platform to support systemic pulmonary shunting procedures. RESULTS: This article showcases state-of-the-art applications and large-scale data analytics in the medical sector employing HPC+ within surgery, medical image processing in diagnostics, nutritional support of patients in hospitals, treating congenital heart diseases in children, and within basic research. CONCLUSION: HPC+ support scientific fields from research to industrial applications in the medical area, enabling researchers to run faster and more complex calculations, simulations and data analyses for the direct benefit of patients, doctors, clinicians and as an accelerator for medical research.

Electrochemically-Switched 2nd Order Non-Linear Optical Response in an Arylimido-Polyoxometalate with High Contrast and Cyclability.

Electrochemically switched 2nd order non-linear optical responses have been demonstrated for the first time in polyoxometalates (POMs), with an arylimido-derivative showing a leading combination of high on/off contrast (94 %), high visible transparency, and cyclability. Spectro-electrochemical and TD-DFT studies indicate that the switch-off results from weakened charge transfer (CT) character of the electronic transitions in the reduced state. This represents the first study of an imido-POM reduced state, and demonstrates the potential of POM hybrids as electrochemically activated molecular switches.

Ultrafast Evaluation of Two-Photon Absorption with Simplified Time-Dependent Density Functional Theory.

This work presents the theoretical background to evaluate two-photon absorption (2PA) cross-sections in the framework of simplified time-dependent density functional theory (sTD-DFT). Our new implementation allows the ultrafast evaluation of 2PA cross-sections for large molecules based on a regular DFT ground-state determinant as well as a variant employing our tight-binding sTD-DFT-xTX flavor for very large systems. The method is benchmarked against higher-level calculations for trans-stilbene and typical fluorescent protein chromophores. For eGFP, a quadrupolar chromophore and its branched version, the flavine mono-nucleotide, and the iLOV protein, we compare sTD-DFT 2PA spectra to experimental ones. This includes extension and testing of our all-atom quantum chemistry methodology for the evaluation of 2PA for a system of ∼2000 atoms, providing striking agreement with the experimental spectrum.

Multi-State Second-Order Nonlinear Optical Switches Incorporating One to Three Benzazolo-Oxazolidine Units: A Quantum Chemistry Investigation.

This contribution employs quantum chemistry methods to describe the variations of the second nonlinear optical responses of molecular switches based on benzazolo-oxazolidine (BOX) units, connected by π-linkers, along their successive opening/closing. Under the fully closed forms, all of them display negligible first hyperpolarizability (ß) values. When one BOX is opened, which is sketched as C→O, a push-pull π-conjugated segment is formed, having the potential to enhance ß and to set the depolarization ratio (DR) to its one-dimensional-like value (DR = 5). This is observed when only one BOX is open, either for the monoBOX species (C→O) or for the diBOX (CC→CO) and triBOX (CCC→CCO) compounds, i.e., when the remaining BOXs stay closed. The next BOX openings have much different effects. For the diBOXs, the second opening (CO→OO) is associated with a decrease of ß, and this decrease is tuned by controlling the conformation of the π-linker, i.e., the centrosymmetry of the whole compound because ß vanishes in centrosymmetric compounds. For the triBOXs, the second opening gives rise to a Λ-shape compound, with a negligible change of ß, but a decrease of the DR whereas, along the third opening, ß remains similar and the DR decreases to the typical value of octupolar systems (DR = 1.5).

Unraveling the Symmetry Effects on the Second-Order Nonlinear Optical Responses of Molecular Switches: The Case of Ruthenium Complexes.

Owing to their odd order, second-order nonlinear optical (NLO) responses are very sensitive to symmetry. Therefore, within hyper-Rayleigh scattering (HRS) technique, the symmetry impacts the amplitude of the molecular responses, the HRS first hyperpolarizability (ßHRS), and the depolarization ratio (DR). Starting from a challenging octupolar structure bearing six ruthenium(II) ammine centers π-conjugated via quaterpyridyl moieties to a tris-chelated zinc(II) core, together with its Λ shape and one-dimensional analogues built by replacing one or two Ru-quaterpyridyl moieties with bipyridine moieties, (time-dependent) density functional theory calculations have been enacted to unravel the symmetry-NLO response relationships as well as their RuII/III redox-triggered switching effects. The one-dimensional and Λ-shaped NLOphores present ßHRS values ∼3 times larger than those of the octupolar system, for both Ru oxidation states. However, using the few-state valence bond-charge transfer models demonstrates that the ßHRS response of the octupolar complex cation can become larger than those of its one-dimensional and Λ-shaped analogues provided stronger donor-acceptor groups are employed. In parallel, the DRs decrease from a strong dipolar character (DR ≈ 6) for the one-dimensional chromophore to a weaker dipolar character (DR ≈ 5) for the Λ-shaped one and to a clear octupolar character (DR ≈ 1.7) for the last one. In all cases, the ß responses originate mostly from metal-to-ligand charge transfer excited states, as revealed using a new scheme for analyzing the variations in electron density upon excitation. The RuII/III oxidations lead to a strong decrease in the ßHRS responses, which is attributed to the loss of the donor character of the Ru centers and therefore to the reduction of the push-pull π-conjugation. These results demonstrate that the NLO contrast and the NLO switching behavior of these Ru cations are maintained for the different molecular symmetries. Finally, the character of the ß responses of the oxidized species, as revealed by the DR values, further evidences a clear evolution from dipolar to octupolar NLOphores.

Self-assembling, structure and nonlinear optical properties of fluorescent organic nanoparticles in water.

Owing to their intense emission, low toxicity and solubility in aqueous medium, fluorescent organic nanoparticles (FONs) have emerged as promising alternatives to inorganic ones for the realization of exogenous probes for bioimaging applications. However, the intimate structure of FONs in solution, as well as the role played by intermolecular interactions on their optical properties, remains challenging to study. Following a recent Second-Harmonic Scattering (SHS) investigation led by two of us [Daniel et al., ACS Photonics, 2015, 2, 1209], we report herein a computational study of the structural organization and second-order nonlinear optical (NLO) properties of FONs based on dipolar chromophores incorporating a hydrophobic triphenylamine electron-donating unit and a slightly hydrophilic aldehyde electron-withdrawing unit at their extremities. Molecular dynamics simulations of the FON formation in water are associated with quantum chemical calculations, to provide insight into the molecular aggregation process, the molecular orientation of the dipolar dyes within the nanoparticles, and the dynamical behavior of their NLO properties. Moreover, the impact of intermolecular interactions on the NLO responses of the FONs is investigated by employing the tight-binding version of the recently developed simplified time-dependent density functional theory (sTD-DFT) approach, allowing the all-atom quantum mechanics treatment of nanoparticles.

All-Atom Quantum Mechanical Calculation of the Second-Harmonic Generation of Fluorescent Proteins.

Fluorescent proteins (FPs) are biotags of choice for second-harmonic imaging microscopy (SHIM). Because of their large size, computing their second-harmonic generation (SHG) response represents a great challenge for quantum chemistry. In this contribution, we propose a new all-atom quantum mechanics methodology to compute SHG of large systems. This is now possible because of two recent implementations: the tight-binding GFN2-xTB method to optimize geometries and a related version of the simplified time-dependent density functional theory (sTD-DFT-xTB) to evaluate quadratic response functions. In addition, a new dual-threshold configuration selection scheme is introduced to reduce the computational costs while retaining overall similar accuracy. This methodology was tested to evaluate the SHG of the proteins iLOV and bacteriorhodopsin (bR). In the case of bR, quantitative agreement with respect to experiment was reached for the out-of-resonance low-energy part of the ßHRS frequency dispersion. This work paves the way toward an accurate prediction of the SHG of large structures-a requirement for the design of new and improved SHIM biotags.

Combining Benzazolo-Oxazolidine Twins toward Multi-state Nonlinear Optical Switches.

Molecular switches are chemical compounds exhibiting the possibility of reversible transformations between their different forms accompanied by a modification in their properties. Among these, switching of multi-addressable Benzazolo-OXazolidines (BOXs) from a closed form to an open form results in drastic modifications in their linear and nonlinear optical properties. Here, we target molecules containing two identical BOX units (DiBOX) connected by different π-conjugated linkers, and we combine synthesis, UV/visible absorption, and hyper-Rayleigh scattering (HRS) measurements, together with density functional theory (DFT) calculations. Three derivatives have been considered, which differ by the linker: (i) a bithiophene moiety (Bt), (ii) two 3,4-ethylenedioxythiopene (EDOT) units, and (iii) a triad composed of an EDOT-thiophene-EDOT sequence (TtO). As a matter of fact, these systems can adopt three states (CF-CF, POF-POF, and CF-POF) depending on the closed form (CF) or the protonated open form (POF) of each BOX unit. Despite chemical equivalence, stepwise switching of such systems under the addition of a chemical acid or an oxidant has been experimentally evidenced for two of them (DiBOX-Bt and DiBOX-TtO). Then, DFT calculations show that the first BOX opening leads to the formation of a push-pull π-conjugated segment, exhibiting a huge increase in the first hyperpolarizability (ß) and a bathochromic shift with respect to the fully closed form. On the contrary, the second BOX opening induces not only a slight bathochromic shift but also a reduction in their ß values conferring the great and uncommon abilities to modulate their linear and nonlinear properties over three discrete levels. Among these results, those on DiBOX-Bt agree with the experimental data obtained by HRS measurements and further shed light on their structure-property relationship.

Performance of DFT functionals for calculating the second-order nonlinear optical properties of dipolar merocyanines.

The second-order nonlinear optical responses of a series of recently designed dipolar merocyanines are investigated using the 2006 Minnesota family of hybrid exchange-correlation functionals (XCFs), as well as the LC-BLYP, ωB97XD and CAM-B3LYP long-range (LR) corrected XCFs. The performance of these different levels of approximation is discussed in regard to reference second-order Møller-Plesset calculations and experimental data obtained from Hyper-Rayleigh Scattering (HRS) measurements. Particular focus is given to the influence of the amount of exact Hartree-Fock exchange included in the XCF on the magnitude of the static HRS responses, as well as to the impact of tuning the range-separation parameter in LR-XCFs, according to a system-specific nonempirical procedure. Frequency dispersion effects are also investigated, as well as their crucial role in the comparison between theoretical and experimental data.

A generalized model for communicating individuality through teleost swim bladder modulation.

Arguments have been made for and against the traditional swim bladder model as a primary component of fish vocalization. This paper presents arguments for decoupled forced and resonant responses being extractable features within a variable air volume. As such, a mechanical analog is used to show how envelope modulation may be used by some species to identify air volume and consequently size in conspecifics. These arguments consider how an arbitrary fish may apply a genetic strategy of forcing vocalization through slow, fast, or both slow and fast sonic musculature while amplitude modulating via swim bladder. The classic resonant bubble model is revised to account for a hypothetical carrier signal resonance associated with static or varying volume. In the absence of live specimens, a test is conducted in different cylindrical structures with equally sized air volumes. First, a proposed method for extraction of swim bladder volume features through blind amplitude demodulated signals in the time and frequency domain is applied. Second, a proposed method for extraction of swim bladder volume features through cyclostationary analysis of the cross-spectral coherent spectra of the modulated and demodulated signal is applied. Both methods take average frequency content as derived by the prescribed signal processing techniques as the input to the correlator functions used to identify air volumes. Vocalizations of Epinephelus guttatus, or more commonly known as the red hind grouper, are used as test signals.

Coupled cluster evaluation of the frequency dispersion of the first and second hyperpolarizabilities of water, methanol, and dimethyl ether.

The static and dynamic first (ß‖) and second (γ‖) hyperpolarizabilities of water, methanol, and dimethyl ether have been evaluated within the response function approach using a hierarchy of coupled cluster levels of approximation and doubly augmented correlation consistent atomic basis sets. For the three compounds, the electronic ß‖ and γ‖ values calculated at the CCSD and CC3 levels are in good agreement with gas phase electric field-induced second harmonic generation (EFISHG) measurements. In addition, for dimethyl ether, the frequency dispersion of both properties follows closely recent experimental values [V. W. Couling and D. P. Shelton, J. Chem. Phys. 143, 224307 (2015)] demonstrating the reliability of these methods and levels of approximation. This also suggests that the vibrational contributions to the EFISHG responses of these molecules are small.

Oxazines: A New Class of Second-Order Nonlinear Optical Switches.

A combined experimental-theoretical investigation has revealed that oxazine-based compounds are multiaddressable, multistate, and multifunctional molecular switches exhibiting contrasts of both linear and second-order nonlinear optical properties. The switching properties are particularly large when the substituent is a donor group. In this study, the cleavage of the C-O bond at the junction of the indole and oxazine cycles (of the closed a forms) is acido-triggered, leading to an open form (b(+)) characterized by larger first hyperpolarizabilities (ßHRS) and smaller excitation energies than in the closed form. These results are confirmed and interpreted utilizing ab initio calculations that have been carried out on a broad set of compounds to unravel the role of the substituent. With respect to acceptor groups, oxazines bearing donor groups are characterized not only by larger ßHRS and ßHRS contrast ratios but also by smaller excitation energies, larger opening-induced charge transfer, and reduction of the bond length alternation, as well as smaller Gibbs energies of the opening reaction. Compared to protonated open forms (b(+)), calculations on the zwitterionic open forms (b) have pointed out similarities in the long-wavelength UV/vis absorption spectra, whereas their ßHRS values might differ strongly as a function of the substituent. Indeed, the open forms present two NLOphores, the indoleninium-substituent entity and the nitrophenol (present in the protonated open form, b(+)) or nitrophenolate (present in the zwitterionic open form, b) moiety. Then, nitrophenolate displays a larger first hyperpolarizability than nitrophenol and the ß tensor of the two entities might reinforce or cancel each other.

Acoustic positioning using a tetrahedral ultrashort baseline array of an acoustic modem source transmitting frequency-hopped sequences.

Acoustic communications and positioning are vital aspects of unmanned underwater vehicle operations. The usage of separate units on each vehicle has become an issue in terms of frequency bandwidth, space, power, and cost. Most vehicles rely on acoustic modems transmitting frequency-hopped multiple frequency-shift keyed sequences for command-and-control operations, which can be used to locate the vehicle with a good level of accuracy without requiring extra signal transmission. In this paper, an ultrashort baseline acoustic positioning technique has been designed, simulated, and tested to locate an acoustic modem source in three dimensions using a tetrahedral, half-wavelength acoustic antenna. The position estimation is performed using the detection sequence contained in each message, which is a series of frequency-hopped pulses. Maximum likelihood estimation of azimuth and elevation estimation is performed using a varying number of pulse and various signal-to-noise ratios. Simulated and measured position estimation error match closely, and indicate that the accuracy of this system improves dramatically as the number of pulses processed increases, given a fixed signal-to-noise ratio.