FROG: Exploiting all-atom molecular dynamics trajectories to calculate linear and non-linear optical responses of molecular liquids within Dalton's QM/MM polarizable embedding scheme.

Quantum mechanical/molecular mechanics (QM/MM) methods are interesting to model the impact of a complex environment on the spectroscopic properties of a molecule. In this context, a FROm molecular dynamics to second harmonic Generation (FROG) code is a tool to exploit molecular dynamics trajectories to perform QM/MM calculations of molecular optical properties. FROG stands for "FROm molecular dynamics to second harmonic Generation" since it was developed for the calculations of hyperpolarizabilities. These are relevant to model non-linear optical intensities and compare them with those obtained from second harmonic scattering or second harmonic generation experiments. FROG's specificity is that it is designed to study simple molecular liquids, including solvents or mixtures, from the bulk to the surface. For the QM/MM calculations, FROG relies on the Dalton package: its electronic-structure models, response theory, and polarizable embedding schemes. FROG helps with the global workflow needed to deal with numerous QM/MM calculations: it permits the user to separate the system into QM and MM fragments, to write Dalton's inputs, to manage the submission of QM/MM calculations, to check whether Dalton's calculation finished successfully, and finally to perform averages on relevant QM observables. All molecules within the simulation box and several time steps are tackled within the same workflow. The platform is written in Python and installed as a package. Intermediate data such as local electric fields or individual molecular properties are accessible to the users in the form of Python object arrays. The resulting data are easily extracted, analyzed, and visualized using Python scripts that are provided in tutorials.

The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism.

Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.

Liquid Water: When Hyperpolarizability Fluctuations Boost and Reshape the Second Harmonic Scattering Intensities.

Second harmonic scattering (SHS) is a method of choice to investigate the molecular structure of liquids. While a clear interpretation of SHS intensity exists for diluted solutions of dyes, the scattering due to solvents remains difficult to interpret quantitatively. Here, we report a quantum mechanics/molecular mechanics (QM/MM) approach to model the polarization-resolved SHS intensity of liquid water, quantifying different contributions to the signal. We point out that the molecular hyperpolarizability fluctuations and correlations cannot be neglected. The intermolecular orientational and hyperpolarizability correlations up to the third solvation layer strongly increase the scattering intensities and modulate the polarization-resolved oscillation that is predicted here by QM/MM without fitting parameters. Our approach can be generalized to other pure liquids to provide a quantitative interpretation of SHS intensities in terms of short-range molecular ordering.

First hyperpolarizability of water in bulk liquid phase: long-range electrostatic effects included via the second hyperpolarizability.

The molecular first hyperpolarizability ß contributes to second-order optical non-linear signals collected from molecular liquids. For the Second Harmonic Generation (SHG) response, the first hyperpolarizability ß(2ω, ω, ω) often depends on the molecular electrostatic environment. This is especially true for water, due to its large second hyperpolarizability γ(2ω, ω, ω,0). In this study we compute the electronic γ(2ω, ω, ω,0) and ß(2ω, ω, ω) for water molecules in liquid water using QM/MM calculations. The average value of γ(2ω, ω, ω,0) is smaller than the one for the gaz phase, and its standard deviation among the molecules is relatively small. In addition, we demonstrate that the average bulk second hyperpolarizability 〈γ(2ω, ω, ω,0)〉 can be used to describe the electrostatic effects of the distant neighborhood on the first hyperpolarizability ß(2ω, ω, ω). In comparison with more complex schemes to take into account long-range effects, the approximation is simple, and does not require any modifications of the QM/MM implementation. The long-range correction can be added explicitly, using an average value of γ for water in the condensed phase. It can also be easily added implicitly in QM/MM calculations through an additional embedding electric field, without the explicit calculation of γ.

First hyperpolarizability of water at the air-vapor interface: a QM/MM study questions standard experimental approximations.

Surface Second-Harmonic Generation (S-SHG) experiments provide a unique approach to probe interfaces. One important issue for S-SHG is how to interpret the S-SHG intensities at the molecular level. Established frameworks commonly assume that each molecule emits light according to an average molecular hyperpolarizability tensor ß(-2ω,ω,ω). However, for water molecules, this first hyperpolarizability is known to be extremely sensitive to their environment. We have investigated the molecular first hyperpolarizability of water molecules within the liquid-vapor interface, using a quantum description with explicit, inhomogeneous electrostatic embedding. The resulting average molecular first hyperpolarizability tensor depends on the distance relative to the interface, and it practically respects the Kleinman symmetry everywhere in the liquid. Within this numerical approach, based on the dipolar approximation, the water layer contributing to the Surface Second Harmonic Generation (S-SHG) intensity is less than a nanometer. The results reported here question standard interpretations based on a single, averaged hyperpolarizability for all molecules at the interface. Not only the molecular first hyperpolarizability tensor significantly depends on the distance relative to the interface, but it is also correlated to the molecular orientation. Such hyperpolarizability fluctuations may impact the S-SHG intensity emitted by an aqueous interface.

Longitudinal position dependence of the second-harmonic generation of optically trapped silica microspheres.

We report the design of a setup combining the simultaneous and independent optical trapping and second-harmonic generation (SHG) of 1 µm diameter silica microspheres with two independent laser beams. Optical trapping is achieved with a tightly focused continuous wave infrared laser beam whereas the SHG intensity from the trapped microparticles is obtained with a 810 nm femtosecond pulsed laser. The silica microparticles are dispersed in an aqueous solution, and a microfluidic channel flow is used to remove untrapped microparticles. We show by the perpendicular displacement of the optical trap from the microfluidic channel wall that it is possible to control the contribution of the channel wall/solution interface to the overall SHG intensity. Stable trapping and SHG detection of two microparticles is also demonstrated. Combining the independent trapping of centrosymmetrical silica microparticles with SHG offers new avenues for analytical studies like surface sensing or all-optical devices where the SHG intensity is controlled by the trapping beam.

Ordering and Nonideality of Air-Ionic Liquid Interfaces in Surface Second Harmonic Generation.

The air-ionic liquid interface for a series of ionic liquids involving imidazolium cations [Cnmim] with different alkyl chain lengths (n = 2, 4, 6, 8, 10, and 12) and the same [NTf2] imide anion has been studied by polarization-resolved second harmonic generation (SHG). An increase as a function of the alkyl chain length of the orientational parameter reveals the increasing ordering of the air-pure ionic liquid interfaces although it is not possible to disentangle the change in mean tilt angle from a change in the tilt angle probability distribution width. Besides, the study of the air-mixed ([C12mim])x([C2mim])1-x[NTf2] ionic liquid interface clearly demonstrates the interfacial nonideality of the mixed ionic liquids. The long alkyl chain cation perturbs the interface as seen from the orientational parameter and displaces the short alkyl chain one for bulk mixture contents as low as 10%. At higher long alkyl chain cation bulk mixture contents, the interface behaves close to a pure long alkyl chain ionic liquid.

Electroosmosis near surfactant laden liquid-air interfaces.

Generation of an electroosmostic (EO) flow near a liquid-gas interface covered with ionic surfactants is experimentally investigated. A combination of microscopic flow measurements with a molecular characterization of the interface by second harmonic generation (SHG) shows that under an electrical forcing, although a liquid flow is generated below the free surface, the surfactants remain immobile. The zeta potential was then determined and compared to the surfactant surface coverage. This combination of experimental techniques opens the route to simultaneously probe the liquid flow near a soapy interface and the corresponding surfactant repartition affecting the hydrodynamic boundary condition.

Multi-scale modeling of mycosubtilin lipopeptides at the air/water interface: structure and optical second harmonic generation.

Monolayers of the lipopeptide mycosubtilin are studied at the air/water interface. Their structure is investigated using molecular dynamics simulations. All-atom models suggest that the lipopeptide is flexible and aggregates at the interface. To achieve simulation times of several microseconds, a coarse-grained (CG) model based on the MARTINI force field was also used. These CG simulations describe the formation of half-micelles at the interface for surface densities up to 1 lipopeptide per nm(2). In these aggregates, the tyrosine side chain orientation is found to be constrained: on average, its main axis, as defined along the C-OH bond, aligns along the interface normal and points towards the air side. The origin of the optical second harmonic generation (SHG) from mycosubtilin monolayers at the air/water interface is also investigated. The molecular hyperpolarizability of the lipopeptide is obtained from quantum chemistry calculations. The tyrosine side chain contribution to the hyperpolarizability is found to be dominant. The orientation distribution of tyrosine, associated with a dominant hyperpolarizability component along the C-OH bond of the tyrosine, yields a ratio of the susceptibility elements χ((2))(ZZZ)/χ((2))(ZXX) consistent with the experimental measurements recently reported by M. N. Nasir et al. [Phys. Chem. Chem. Phys., 2013, 15, 19919].

Reorientation of the helix of the tryptophan-rich gp41W peptide from HIV-1 at interfaces.

The glycoprotein gp41 from the Human Immunodeficiency Virus type 1 (HIV-1) has an amino acid sequence enriched in tryptophan residues, the so-called gp41W peptide (i.e., KWASLWNWFNITNWLWYIK) and plays a crucial role in HIV-1 host cell infection. Using the coupling of Second Harmonic Generation targeting the tryptophan residues with lateral surface tension measurements, we investigate the interaction of gp41W with a neat air∕water and a lipid∕water interfaces. At the air∕water interface, gp41W presents a well-defined orientation and this orientation is strongly modified at the lipid∕water interface, depending on the surface pressure. These results show that this strategy is well suited to monitor tryptophan containing α-helices orientation at lipid∕water interfaces.

Influence of the tyrosine environment on the second harmonic generation of iturinic antimicrobial lipopeptides at the air-water interface.

The second harmonic generation (SHG) response at the air-water interface from the tyrosine-containing natural iturinic cyclo-lipopeptides mycosubtilin, iturin A and bacillomycin D is reported. It is shown that this response is dominated by the single tyrosine residue present in these molecules owing to the large first hyperpolarizability arising from the non-centrosymmetric aromatic ring structure of this amino acid. The SHG response of these iturinic antibiotics is also compared to the response of surfactin, a cyclo-lipopeptide with a similar l,d-amino acid sequence but lacking a tyrosine residue, and PalmATA, a synthetic linear lipopeptide possessing a single tyrosine residue but lacking the amino acid sequence structuring the cycle of the iturinic antibiotics. From the light polarization analysis of the SHG response, it is shown that the tyrosine local environment is critical in defining the SHG response of these peptides at the air-water interface. Our results demonstrate that tyrosine, similar to tryptophan, can be used as an endogenous molecular probe of peptides and proteins for SHG at the air-water interface, paving the way for SHG studies of other tyrosine-containing bioactive molecules.

A bottom-up approach to build the hyperpolarizability of peptides and proteins from their amino acids.

We experimentally demonstrate that some peptides and proteins lend themselves to an elementary analysis where their first hyperpolarizability can be decomposed into the coherent superposition of the first hyperpolarizability of their elementary units. We then show that those elementary units can be associated with the amino acids themselves in the case of nonaromatic amino acids and nonresonant second harmonic generation. As a case study, this work investigates the experimentally determined first hyperpolarizability of rat tail Type I collagen and compares it to that of the shorter peptide [(PPG)10]3, where P and G are the one-letter code for Proline and Glycine, respectively, and that of the triamino acid peptides PPG and GGG. An absolute value of (0.16 ± 0.01) × 10(-30) esu for the first hyperpolarizability of nonaromatic amino acids is then obtained by using the newly defined 0.087 × 10(-30) esu reference value for water. By using a collagen like model, the microscopic hyperpolarizability along the peptide bond can be evaluated at (0.7 ± 0.1) × 10(-30) esu.

Sensing with multipolar second harmonic generation from spherical metallic nanoparticles.

We show that sensing in the nonlinear optical regime using multipolar surface plasmon resonances is more sensitive in comparison to sensing in the linear optical regime. Mie theory, and its extension to the second harmonic generation from a metallic nanosphere, is used to describe multipolar second harmonic generation from silver metallic nanoparticles. The standard figure of merit of a potential plasmonic sensor based on this principle is then calculated. We finally demonstrate that such a sensor is more sensitive to optical refraction index changes occurring in the vicinity of the metallic nanoparticle than its linear counterpart.

Effect of a thioalkane capping layer on the first hyperpolarizabilities of gold and silver nanoparticles.

We have measured the first hyperpolarizabilities of thioalkane capped silver and gold metallic nanoparticles. The values found are ß(AgC 12-10 nm) = (2.10 ± 0.23) × 10(-26) esu for 10 nm diameter silver nanoparticles and ß(AuC 18-18 nm) = (3.37 ± 0.08) × 10(-26) esu for 18 nm diameter gold nanoparticles at the fundamental wavelength of 784 nm. By comparison to the corresponding values reported for citrate capped silver and gold metallic nanoparticles, after size corrections, decreases by factors of 4.3 and 6.5 respectively are observed. These decreases are tentatively attributed to the bonds formed between the gold and silver surface atoms and the sulfur atoms of the capping layer.

Three-dimensional mapping of single gold nanoparticles embedded in a homogeneous transparent matrix using optical second-harmonic generation.

We report the three-dimensional mapping of 150 nm gold metallic nanoparticles dispersed in a homogeneous transparent polyacrylamide matrix using second-harmonic generation. We demonstrate that the position of single nanoparticles can be well defined using only one incident fundamental beam and the harmonic photon detection performed at right angle. The fundamental laser beam properties are determined using its spatial autocorrelation function and used to prove that single nanoparticles are observed. Polarization resolved measurements are also performed allowing for a clear separation of the second-harmonic response of the single gold metallic nanoparticles from that of aggregates of such nanoparticles.

Optical second harmonic generation of single metallic nanoparticles embedded in a homogeneous medium.

We report the optical second harmonic generation from individual 150 nm diameter gold nanoparticles dispersed in gelatin. The quadratic hyperpolarizability of the particles is determined and the input polarization dependence of the second harmonic intensity obtained. These results are found in excellent agreement with ensemble measurements and finite element simulations. These results open up new perspectives for the investigation of the nonlinear optical properties of noble metal nanoparticles.

Measurement of the second-order hyperpolarizability of the collagen triple helix and determination of its physical origin.

We performed Hyper-Rayleigh Scattering (HRS) experiments to measure the second-order nonlinear optical response of the collagen triple helix and determine the physical origin of second harmonic signals observed in collagenous tissues. HRS experiments yielded a second-order hyperpolarizability of 1.25 x 10(-27) esu for rat-tail type I collagen, a surprisingly large value considering that collagen presents no strong harmonophore in its amino acid sequence. Polarization-resolved experiments showed intramolecular coherent contributions to the HRS signal along with incoherent contributions that are the only contributions for molecules with dimensions much smaller than the excitation wavelength. We therefore modeled the effective second-order hyperpolarizability of the 290 nm long collagen triple helix by summing coherently the nonlinear response of well-aligned moieties along the triple helix axis. This model was confirmed by HRS measurements after denaturation of the collagen triple helix and for a collagen-like short model peptide [(Pro-Pro-Gly)(10)](3). We concluded that the large collagen nonlinear response originates in the tight alignment of a large number of small and weakly efficient harmonophores, presumably the peptide bonds, resulting in a coherent amplification of the nonlinear signal.

Investigating the interaction of crystal violet probe molecules on sodium dodecyl sulfate micelles with hyper-Rayleigh scattering.

We report the use of the nonlinear optical technique of hyper-Rayleigh scattering to investigate the interaction of the cationic probe molecule crystal violet with micelles of sodium dodecyl sulfate. An absolute value of (847 +/- 80) x 10(-30) esu is measured at the fundamental wavelength of 870 nm for the molecular hyperpolarizability of crystal violet free in pure aqueous solutions. In aqueous solutions of sodium dodecyl sulfate, above and below the critical micelle concentration, the measured hyperpolarizability of crystal violet is weaker than in the solution free of sodium dodecyl sulfate. From the comparison with linear optical photoabsorption spectroscopy data, this difference is attributed to electrostatic interactions between the cationic crystal violet molecules and the negatively charged sodium dodecyl sulfate surfactant molecules present in excess. Polarization resolved hyper-Rayleigh scattering measurements are then performed to show that, below and above the critical micelle concentration, crystal violet molecules also undergo symmetry changes upon interaction with sodium dodecyl sulfate. Above the critical micelle concentration, the minimum fraction of micelles interacting with at least one CV molecule is estimated. For instance, for a crystal violet aqueous concentration of 150 microM, this fraction is larger than 7%.

Wavelength dependence of the hyper Rayleigh scattering response from gold nanoparticles.

The wavelength dependence of the quadratic hyperpolarizability of 11 nm diam gold nanoparticles, is reported as measured by hyper Rayleigh scattering. An important photoluminescence background underlying the hyper Rayleigh signal is observed, a contribution attributed to radiative electron-hole recombinations following multiphoton excitation favored by adsorbed organic compound like citrate on the surface of the nanoparticles. The absolute value of the quadratic hyperpolarizability of gold spherical nanoparticles is determined and a strong enhancement is observed for harmonic frequencies in resonance with the dipolar surface plasmon excitation. No contribution of the interband transition is observed. The absolute values reported, beta(C)=5.1x10(-26) esu at the second harmonic energy 2.39 eV, have been measured with femtosecond long laser pulse, and are 1 order of magnitude weaker that the one previously reported with nanosecond long pulses. This difference can be related to similar measurements performed on the second order hyperpolarizability of gold nanoparticles and may be attributed to different electronic relaxation regimes. Finally, the spectrum of the quadratic hyperpolarizability is compared to the theoretically expected one.

Hyper-Rayleigh scattering of gold nanorods and their relationship with linear assemblies of gold nanospheres.

The surface plasmon enhanced hyper-Rayleigh scattering light collected from an aqueous solution of gold nanorods is reported. A non negligible part of the signal is attributed to a photoluminescence background attributed to the electron hole recombination following multiphoton excitation of d-valence band electrons into the sp-conduction band. This radiative relaxation process is likely favored by the presence of the organic species adsorbed at the surface of the nanorods. The absolute value for the hyperpolarisability of nanorods is also compared by the external reference method to that of para-nitroaniline and found to be rather large although an absolute value cannot be given because the exact number density of the gold nanorods is unaccessible. This value is however compared with values reported for linear assemblies of gold spherical nanoparticles and further support the simple model of gold metal ellipsoids to describe the hyper-Rayleigh light intensities. The polarisation analysis of the hyper-Rayleigh scattering light is also determined for gold nanorods and compared to the expected one for gold nanospheres. For the latter spheres, the weakness of the signal intensities precludes a definite comparison with the model. On the opposite, for the nanorods, the polarisation dependence of the hyper-Rayleigh scattered light clearly deviates from the one expected for nanospheres.