Twin-to-Twin Transfusion Syndrome: Diagnostic Imaging and Its Role in Staving Off Malpractice Charges and Litigation.

The study aims to expound upon the imaging-based diagnostic methodologies aimed at identifying twin-to-twin transfusion syndrome (TTTS), a serious, somewhat rare prenatal condition that takes place in pregnancies where identical twins, or other multiples, share a placenta (monochorionic placenta), highlighting how medico-legal outcomes can be affected by provable compliance with consolidated diagnostic guidelines or best practices. It is of utmost importance to produce a prompt identification of TTTS instances; an early diagnosis is in fact critical in order to effectively treat and manage TTTS. By virtue of TTTS being a highly progressive condition, a delay in diagnosis can result in disastrous outcomes; just a few weeks delay in the diagnosis of TTTS can turn out fatal for one or both twins. Hence, most TTTS malpractice claims involve allegations of medical negligence, namely the failure to recognize the condition in a timely fashion, or to proceed with adequate diagnostic and therapeutic pathways. In that regard, case law databases have been pored over (Justia, Lexis, Leagle), and five significant court cases have been examined and discussed in an attempt to identify objective medico-legal standards and bring to the forefront relevant forensic dynamics. In fact, when health professionals are capable of proving adherence to guidelines or best practices, this can shield them from malpractice allegations and ensuing litigation.

Coupling to Charge Transfer States is the Key to Modulate the Optical Bands for Efficient Light Harvesting in Purple Bacteria.

The photosynthetic apparatus of purple bacteria uses exciton delocalization and static disorder to modulate the position and broadening of its absorption bands, leading to efficient light harvesting. Its main antenna complex, LH2, contains two rings of identical bacteriochlorophyll pigments, B800 and B850, absorbing at 800 and 850 nm, respectively. It has been an unsolved problem why static disorder of the strongly coupled B850 ring is several times larger than that of the B800 ring. Here we show that mixing between excitons and charge transfer states in the B850 ring is responsible for the effect. The linear absorption spectrum of the LH2 system is simulated by using a multiscale approach with an exciton Hamiltonian generalized to include the charge transfer states that involve adjacent pigment pairs, with static disorder modeled microscopically by molecular dynamics simulations. Our results show that sufficient inhomogeneous broadening of the B850 band, needed for efficient light harvesting, is only obtained by utilizing static disorder in the coupling between local excited and interpigment charge transfer states.

Shaping excitons in light-harvesting proteins through nanoplasmonics.

Nanoplasmonics has been used to enhance molecular spectroscopic signals, with exquisite spatial resolution down to the sub-molecular scale. By means of a rigorous, state-of-the-art multiscale model based on a quantum chemical description, here we show that optimally tuned tip-shaped metal nanoparticles can selectively excite localized regions of typically coherent systems, eventually narrowing down to probing one single pigment. The well-known major light-harvesting complex LH2 of purple bacteria has been investigated because of its unique properties, as it presents both high and weak delocalization among subclusters of pigments. This finding opens the way to the direct spectroscopic investigation of quantum-based processes, such as the quantum diffusion of the excitation among the chromophores, and their external manipulation.

Coupling Real-Time Time-Dependent Density Functional Theory with Polarizable Force Field.

Real-time time-dependent density functional theory (RT-TDDFT) is a powerful tool for obtaining spectroscopic observables and understanding complex, time-dependent properties. Currently, performing RT-TDDFT calculations on large, fully quantum mechanical systems is not computationally feasible. Previously, polarizable mixed quantum mechanical and molecular mechanical (QM/MMPol) models have been successful in providing accurate, yet efficient, approximations to a fully quantum mechanical system. Here we develop a coupling scheme between induced dipole based QM/MMPol and RT-TDDFT. Our approach is validated by comparing calculated spectra with both real-time and linear-response TDDFT calculations. The model developed within provides an accurate method for performing RT-TDDFT calculations on extended systems while accounting for mutual polarization between the quantum mechanical and molecular mechanical regions.

Hybrid QM/MM Molecular Dynamics with AMOEBA Polarizable Embedding.

We present the implementation of a Born-Oppenheimer (BO) hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) strategy using density functional theory (DFT) and the polarizable AMOEBA force field. This approach couples the Gaussian and Tinker suite of programs through a variational formalism allowing for a full self-consistent relaxation of both the AMOEBA induced dipoles and the DFT electron density at each MD step. As the DFT SCF cycles are the limiting factor in terms of computational efforts and MD stability, we focus on the latter aspect and compare the time-reversible BO (TR-BO) and the extended BO Lagrangian approaches (XL-BO) to the MD propagation. The XL-BO approach allows for stable, energy-conserving trajectories offering various perspectives for hybrid simulations using polarizable force fields.

Excited-State Gradients in Polarizable QM/MM Models: An Induced Dipole Formulation.

Charge and structural relaxation of electronically excited states in embedded systems are strongly affected by the environment. It is known that the largest part of environment effects comes from electrostatics. However, polarization can also play a role by tuning the electronic and geometrical properties of the states, finally modifying the fluorescence. Here we present the formulation of analytical excited-state gradients within a polarizable QM/MM approach and their implementation within the ONIOM framework. A time-dependent DFT level of theory is used in combination with an induced dipole formulation of the polarizable embedding. The formation and relaxation of the bright excited state of an organic dye (DAPI) intercalated in a DNA pocket is used to quantify the role played by the mutual polarization between the QM subsystem and the embedding and also to investigate the onset of overpolarization, which is a known limit of the model with potentially detrimental effects. On the one hand, the results indicate the robustness of the QM-classical interface and, on the other hand, show the non-negligible effect of polarization between DAPI and a DNA pocket in determining the fluorescence properties of the embedded dye.

Theoretical description of protein field effects on electronic excitations of biological chromophores.

Photoinitiated phenomena play a crucial role in many living organisms. Plants, algae, and bacteria absorb sunlight to perform photosynthesis, and convert water and carbon dioxide into molecular oxygen and carbohydrates, thus forming the basis for life on Earth. The vision of vertebrates is accomplished in the eye by a protein called rhodopsin, which upon photon absorption performs an ultrafast isomerisation of the retinal chromophore, triggering the signal cascade. Many other biological functions start with the photoexcitation of a protein-embedded pigment, followed by complex processes comprising, for example, electron or excitation energy transfer in photosynthetic complexes. The optical properties of chromophores in living systems are strongly dependent on the interaction with the surrounding environment (nearby protein residues, membrane, water), and the complexity of such interplay is, in most cases, at the origin of the functional diversity of the photoactive proteins. The specific interactions with the environment often lead to a significant shift of the chromophore excitation energies, compared with their absorption in solution or gas phase. The investigation of the optical response of chromophores is generally not straightforward, from both experimental and theoretical standpoints; this is due to the difficulty in understanding diverse behaviours and effects, occurring at different scales, with a single technique. In particular, the role played by ab initio calculations in assisting and guiding experiments, as well as in understanding the physics of photoactive proteins, is fundamental. At the same time, owing to the large size of the systems, more approximate strategies which take into account the environmental effects on the absorption spectra are also of paramount importance. Here we review the recent advances in the first-principle description of electronic and optical properties of biological chromophores embedded in a protein environment. We show their applications on paradigmatic systems, such as the light-harvesting complexes, rhodopsin and green fluorescent protein, emphasising the theoretical frameworks which are of common use in solid state physics, and emerging as promising tools for biomolecular systems.

An Ab Initio Description of the Excitonic Properties of LH2 and Their Temperature Dependence.

The spectroscopic properties of light-harvesting (LH) antennae in photosyntehtic organisms represent a fingerprint that is unique for each specific pigment-protein complex. Because of that, spectroscopic observations are generally combined with structural data from X-ray crystallography to obtain an indirect representation of the excitonic properties of the system. Here, an alternative strategy is presented which goes beyond this empirical approach and introduces an ab initio computational description of both structural and electronic properties and their dependence on the temperature. The strategy is applied to the peripheral light-harvesting antenna complex (LH2) present in purple bacteria. By comparing this model with the one based on the crystal structure, a detailed, molecular level explanation of the absorption and circular dichroism (CD) spectra and their temperature dependence is achieved. The agreement obtained with the experiments at both low and room temperature lays the groundwork for an atomistic understanding of the excitation dynamics in the LH2 system.

A QM/MM Approach Using the AMOEBA Polarizable Embedding: From Ground State Energies to Electronic Excitations.

A fully polarizable implementation of the hybrid quantum mechanics/molecular mechanics approach is presented, where the classical environment is described through the AMOEBA polarizable force field. A variational formalism, offering a self-consistent relaxation of both the MM induced dipoles and the QM electronic density, is used for ground state energies and extended to electronic excitations in the framework of time-dependent density functional theory combined with a state specific response of the classical part. An application to the calculation of the solvatochromism of the pyridinium N-phenolate betaine dye used to define the solvent ET(30) scale is presented. The results show that the QM/AMOEBA model not only properly describes specific and bulk effects in the ground state but it also correctly responds to the large change in the solute electronic charge distribution upon excitation.

Control of Coherences and Optical Responses of Pigment-Protein Complexes by Plasmonic Nanoantennae.

The key for light-harvesting in pigment-protein complexes are molecular excitons, delocalized excited states comprising a superposition of excitations at different molecular sites. There is experimental evidence that the optical response due to such excitons can be largely affected by plasmonic nanoantennae. Here we employ a multiscale approach combining time-dependent density functional theory and polarizable classical models to study the optical behavior of the LH2 complex present in bacteria when interacting with a gold nanorod. The simulation not only reproduces the experiments but also explains their molecular origin. By tuning the chromophoric unit and selectively switching on/off the excitonic interactions, as well as by exploring different setups, we clearly show that the dramatic enhancement in the optical response, unexpectedly, is not accompanied by changes in the coherences. Instead polarization effects are dominant. These results can be used to design an optimal control of the light-harvesting process through plasmonic nanoantennae.

Photoprotection and triplet energy transfer in higher plants: the role of electronic and nuclear fluctuations.

Photosynthetic organisms employ several photoprotection strategies to avoid damage due to the excess energy in high light conditions. Among these, quenching of triplet chlorophylls by neighboring carotenoids (Cars) is fundamental in preventing the formation of singlet oxygen. Cars are able to accept the triplets from chlorophylls by triplet energy transfer (TET). We have here studied TET rates in CP29, a minor light-harvesting complex (LHC) of the Photosystem II in plants. A fully atomistic strategy combining classical molecular dynamics of the LHC in its natural environment with a hybrid time-dependent density functional theory/polarizable MM description of the TET is used. We find that the structural fluctuations of the pigment-protein complex can largely enhance the transfer rates with respect to those predicted using the crystal structure, reducing the triplet quenching times in the subnanosecond scale. These findings add a new perspective for the interpretation of the photoprotection function and its relation with structural motions of the LHC.

Achieving linear scaling in computational cost for a fully polarizable MM/continuum embedding.

In this paper, we present a new, efficient implementation of a fully polarizable QM/MM/continuum model based on an induced-dipoles polarizable force field and on the Conductor-like Screening Model as a polarizable continuum in combination with a self-consistent field QM method. The paper focuses on the implementation of the MM/continuum embedding, where the two polarizable methods are fully coupled to take into account their mutual polarization. With respect to previous implementations, we achieve for the first time a linear scaling with respect to both the computational cost and the memory requirements without limitations on the molecular cavity shape. This is achieved thanks to the use of the recently developed ddCOSMO model for the continuum and the Fast Multipole Method for the force field, together with an efficient iterative procedure. Therefore, it becomes possible to include in the classical layer as much as several tens of thousands of atoms with a limited computational effort.

Plasmon enhanced light harvesting: multiscale modeling of the FMO protein coupled with gold nanoparticles.

Plasmonic systems, such as metal nanoparticles, are becoming increasingly important in spectroscopies and devices because of their ability to enhance, even by several orders of magnitude, the photophysical properties of neighboring systems. In particular, it has been shown both theoretically and experimentally that combining nanoplasmonic devices with natural light-harvesting proteins substantially increases the fluorescence and absorption properties of the system. This kind of biohybrid device can have important applications in the characterization and design of efficient light-harvesting systems. In the present work, the FMO light-harvesting protein was combined with gold nanoparticles of different sizes, and its photophysical properties were characterized using a multiscale quantum-mechanical classical-polarizable and continuum model (QM/MMPol/PCM). By optimal tuning of the plasmon resonance of the metal nanoparticles, fluorescence enhancements of up to 2 orders of magnitude were observed. Orientation effects were found to be crucial: amplifications by factors of up to 300 were observed for the absorption process, while the radiative decay of the emitting state increased at most by a factor of 10, mostly as a result of poor alignment of the emitting state with the considered metal aggregates. Despite being a limiting factor for high-fluorescence-enhancement devices, the strong orientation dependence may represent an important feature of the natural light-harvesting system that could allow selective enhancement of a specific excited state of the complex.

Excitation energy transfer in donor-bridge-acceptor systems: a combined quantum-mechanical/classical analysis of the role of the bridge and the solvent.

The technical application of excitation energy transfer requires a fine control of the geometry of the system. This can be achieved by introducing a chemical bridge between the donor and acceptor moieties that can be tuned in its chemical properties and its length. In such donor-bridge-acceptor systems, however, the role of the bridge in enhancing or depleting the energy transfer efficiency is not easy to predict. Here we propose a computational strategy based on the combination of time-dependent density functional theory, polarizable molecular mechanics and continuum approaches. The resulting three-layer model when applied to the study of the energy transfer process in different porphyrin-based systems, each characterized by a specific donor/acceptor pair and various types of bridges, allows us to dissect the role of through-bond and through-space mechanisms and clarify their dependence on the nature and length of the bridge as well as on the presence of a solvent.

Geometry Optimization in Polarizable QM/MM Models: The Induced Dipole Formulation.

We present the mathematical derivation and the computational implementation of the analytical geometry derivatives for a polarizable QM/MM model (QM/MMPol). In the adopted QM/MMPol model, the focused part is treated at QM level of theory, while the remaining part (the environment) is described classically as a set of fixed charges and induced dipoles. The implementation is performed within the ONIOM procedure, resulting in a polarizable embedding scheme, which can be applied to solvated and embedded systems and combined with different polarizable force fields available in the literature. Two test cases characterized by strong hydrogen-bond and dipole-dipole interactions, respectively, are used to validate the method with respect to the nonpolarizable one. Finally, an application to geometry optimization of the chromophore of Rhodopsin is presented to investigate the impact of including mutual polarization between the QM and the classical parts in conjugated systems.

Toward a Unified Modeling of Environment and Bridge-Mediated Contributions to Electronic Energy Transfer: A Fully Polarizable QM/MM/PCM Approach.

Recent studies have unveiled the similar nature of solvent (screening) effects and bridge-mediated contributions to electronic energy transfer, both related to the bridge/solvent polarizability properties. Here, we exploit the similarity of such contributions to develop a fully polarizable mixed QM/discrete/continuum model aimed at studying electronic energy transfer processes in supramolecular systems. In the model, the definition of the three regions is completely flexible and allows us to explore the possibility to describe bridge-mediated contributions by using a polarizable MM description of the linker. In addition, we show that the classical MMPol description of the bridge can be complemented either with an analogous atomistic or with a continuum description of the solvent. Advantages and drawbacks of the model are finally presented and discussed with respect to the system under study.

Quantum mechanical study of the solvent-dependence of electronic energy transfer rates in a Bodipy closely-spaced dyad.

The ability of Förster theory to describe electronic energy transfer rates, and their solvent-dependence, have been studied theoretically in a series of 15 solvents of varying degrees of polarity for a rigid closely-spaced dyad, constituted by two boron dipyrromethene dyes, which was recently studied experimentally by Harriman & Ziessel, Photochem. Photobiol. Sci., 2010, 9, 960. We use time-dependent density functional theory calculations coupled to the polarizable continuum model to analyse the solvent-dependence of the spectroscopic and energy transfer properties of the system. This methodology allows us to examine the impact of the solvent on both electronic (solvent screening) and structural (dipole separation and orientation) factors by consistently incorporating solvent effects in the determination of molecular geometries, transition densities, and electronic couplings. In addition, we analyse the impact of bridge-mediated contributions to the electronic interaction between the dyes. We are therefore able to assess whether a Förster-type point-dipole approximation is valid for the molecular system studied.

Theoretical investigation of the mechanism and dynamics of intramolecular coherent resonance energy transfer in soft molecules: a case study of dithia-anthracenophane.

A computational study is conducted on dithia-anthracenophane (DTA), for which there is experimental evidence for coherent resonance energy transfer dynamics, and on dimethylanthracene (DMA), a molecule representing the energy donor and the acceptor in DTA. Electronic excitation energies are calculated by configuration interaction singles (CIS) and time-dependent density functional theory (TD-DFT) methods and are compared to experimental ones. Electronic coupling constants are calculated between two DMAs embedded into the ground-state structure of DTA employing methods based on transition densities. The resulting values of electronic coupling provide a more consistent interpretation of experiments than those based on one-half the level spacing of DTA excitation energies. Solvation effects are studied based on the polarizable continuum model (PCM). Solvent-induced polarization and screening effects are shown to make opposite contributions, and the net electronic coupling is little different from the value in a vacuum. The likelihood of coherent population transfer is assessed on the basis of a recently developed theory of coherent resonance energy transfer. The time scale of bath is shown to have an important role in sustaining the quantum coherence. The combination of quantum chemical and dynamical data suggests that the electronic coupling in DTA is in the range of 50-100 cm(-1). The presence of oscillatory excitation population dynamics can be understood from the picture of polaronic excitation moderately dressed with dispersive vibrational modes. The effect of torsional modulation on the excitation energies of DTA and electronic coupling is examined on the basis of optimized structures with the torsional angle constrained. The result suggests that inelastic effect due to torsional motion cannot be disregarded in DTA.