Light-Induced Function

Light-Induced Function

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From Excitation to Signal

From Excitation to Signal

#LIFETimeS #website
Through Time and Space

Through Time and Space

#LIFETimeS #WebSite
Light-Induced Function

Light-Induced Function

#LIFETimeS #WebSite
From Excitation to Signal

From Excitation to Signal

#LIFETimeS #WebSite
Through Time and Space

Through Time and Space

#LIFETimeS #WebSite


Pedraza-González, L., Cignoni, E., D'Ascenzi, J., Cupellini, L. & Mennucci, B.
How the pH Controls Photoprotection in the Light-Harvesting Complex of Mosses
J. Am. Chem. Soc. 145, 13, 7482–7494 (2023).<Read>
In response to varying light conditions, light-harvesting complexes (LHCs) switch from a light-harvesting state to a quenched state to protect the photosynthetic organism from excessive light irradiation in a strategy known as nonphotochemical quenching (NPQ). NPQ is activated by an acidification of the thylakoid lumen, which is sensed directly or indirectly by the LHC, resulting in a conformational change of the complex that leads to the quenched state. The conformational changes responsible for NPQ activation and their connection to specific quenching mechanisms are still unknown. Here, we investigate the pH-triggered conformational changes in the light-harvesting complex stress-related (LHCSR) of mosses. By combining constant-pH molecular dynamics and enhanced sampling techniques, we find that the pH sensitivity of the complex is driven by the coupled protonation of three residues modulating the conformation of the short amphipathic helix placed at the lumen side of the embedding membrane. Combining these results with quantum mechanics/molecular mechanics calculations, we show that the quenching mechanism sensitive to the pH goes through a charge-transfer between a carotenoid and an excited chlorophyll, which is controlled by the protein conformation.
Cignoni, E., Cupellini, L., Mennucci, B. 
Machine Learning Exciton Hamiltonians in Light-Harvesting Complexes
J Chem Theory Comput 19, 3, 965–977 (2023).<Read>
We propose a machine learning (ML)-based strategy for an inexpensive calculation of excitonic properties of light-harvesting complexes (LHCs). The strategy uses classical molecular dynamics simulations of LHCs in their natural environment in combination with ML prediction of the excitonic Hamiltonian of the embedded aggregate of pigments. The proposed ML model can reproduce the effects of geometrical fluctuations together with those due to electrostatic and polarization interactions between the pigments and the protein. The training is performed on the chlorophylls of the major LHC of plants, but we demonstrate that the model is able to extrapolate well beyond the initial training set. Moreover, the accuracy in predicting the effects of the environment is tested on the simulation of the small changes observed in the absorption spectra of the wild-type and a mutant of a minor LHC.



Lipparini, F., Mennucci, B. 
Hybrid QM/classical models: Methodological advances and new applications 
Chem Phys Rev 2, 041303 (2021).<Read>
Hybrid methods that combine quantum mechanical descriptions with classical models are very popular in molecular modeling. Such a large diffusion reflects their effectiveness, which over the years has allowed the quantum mechanical description to extend its boundaries to systems of increasing size and to processes of increasing complexity. Despite this success, research in this field is still very active and a number of advances have been made recently, further extending the range of their applications. In this review, we describe such advances and discuss how hybrid methods may continue to improve in the future. The various formulations proposed so far are presented here in a coherent way to underline their common methodological aspects. At the same time, the specificities of the different classical models and of their coupling with the quantum mechanical domain are highlighted and discussed, with special attention to the computational and numerical aspects.
Hashem, S. Macaluso, V., Nottoli, M., Lipparini, F., Cupellini, L., Mennucci B.
From crystallographic data to the solution structure of photoreceptors: the case of the AppA BLUF domain 
Chem Sci 12, 13331–13342 (2021).<Read>
Photoreceptor proteins bind a chromophore, which, upon light absorption, modifies its geometry or its interactions with the protein, finally inducing the structural change needed to switch the protein from an inactive to an active or signaling state. In the Blue Light-Using Flavin (BLUF) family of photoreceptors, the chromophore is a flavin and the changes have been connected with a rearrangement of the hydrogen bond network around it on the basis of spectroscopic changes measured for the dark-to-light conversion. However, the exact conformational change triggered by the photoexcitation is still elusive mainly because a clear consensus on the identity not only of the light activated state but also of the dark one has not been achieved. Here, we present an integrated investigation that combines microsecond MD simulations starting from the two conflicting crystal structures available for the AppA BLUF domain with calculations of NMR, IR and UV-Vis spectra using a polarizable QM/MM approach. Thanks to such a combined analysis of the three different spectroscopic responses, a robust characterization of the structure of the dark state in solution is given together with the uncovering of important flaws of the most popular molecular mechanisms present in the literature for the dark-to-light activation.
Nottoli, M., Nifosì, R., Mennucci, B., Lipparini, F.
Energy, Structures, and Response Properties with a Fully Coupled QM/AMOEBA/ddCOSMO Implementation 
J Chem Theory Comput 17, 5661–5672 (2021).<Read>
We present the implementation of a fully coupled polarizable QM/MM/continuum model based on the AMOEBA polarizable force field and the domain decomposition implementation of the conductor-like screening model. Energies, response properties, and analytical gradients with respect to both QM and MM nuclear positions are available, and a generic, atomistic cavity can be employed. The model is linear scaling in memory requirements and computational cost with respect to the number of classical atoms and is therefore suited to model large, complex systems. Using three variants of the green-fluorescent protein, we investigate the overall computational cost of such calculations and the effect of the continuum model on the convergence of the computed properties with respect to the size of the embedding. We also demonstrate the fundamental role of polarization effects by comparing polarizable and nonpolarizable embeddings to fully QM ones.
Macaluso, V., Hashem, S., Nottoli, M., Lipparini, F., Cupellini, L., Mennucci B. 
Ultrafast Transient Infrared Spectroscopy of Photoreceptors with Polarizable QM/MM Dynamics. 
J Phys Chem B 125, 10282–10292 (2021).<Read>
Ultrafast transient infrared (TRIR) spectroscopy is widely used to measure the excitation-induced structural changes of protein-bound chromophores. Here, we design a novel and general strategy to compute TRIR spectra of photoreceptors by combining μs-long MM molecular dynamics with ps-long QM/AMOEBA Born–Oppenheimer molecular dynamics (BOMD) trajectories for both ground and excited electronic states. As a proof of concept, the strategy is here applied to AppA, a blue-light-utilizing flavin (BLUF) protein, found in bacteria. We first analyzed the short-time evolution of the embedded flavin upon excitation revealing that its dynamic Stokes shift is ultrafast and mainly driven by the internal reorganization of the chromophore. A different normal-mode representation was needed to describe ground- and excited-state IR spectra. In this way, we could assign all of the bands observed in the measured transient spectrum. In particular, we could characterize the flavin isoalloxazine-ring region of the spectrum, for which a full and clear description was missing.
Bondanza, M., Jacquemin, D., Mennucci, B
Excited States of Xanthophylls Revisited: Toward the Simulation of Biologically Relevant Systems. 
J Phys Chem Lett 12, 6604–6612 (2021).<Read>
Xanthophylls are a class of oxygen-containing carotenoids, which play a fundamental role in light-harvesting pigment–protein complexes and in many photoresponsive proteins. The complexity of the manifold of the electronic states and the large sensitivity to the environment still prevent a clear and coherent interpretation of their photophysics and photochemistry. In this Letter, we compare cutting-edge ab initio methods (CC3 and DMRG/NEVPT2) with time-dependent DFT and semiempirical CI (SECI) on model keto-carotenoids and show that SECI represents the right compromise between accuracy and computational cost to be applied to real xanthophylls in their biological environment. As an example, we investigate canthaxanthin in the orange carotenoid protein and show that the conical intersections between excited states and excited–ground states are mostly determined by the effective bond length alternation coordinate, which is significantly tuned by the protein through geometrical constraints and electrostatic effects.
Nottoli, M., Bondanza, M., Lipparini, F., Mennucci, B.
An enhanced sampling QM/AMOEBA approach: The case of the excited state intramolecular proton transfer in solvated 3-hydroxyflavone
J. Chem. Phys. 154, 184107 (2021).  <Read>
We present an extension of the polarizable quantum mechanical (QM)/AMOEBA approach to enhanced sampling techniques. This is achieved by connecting the enhanced sampling PLUMED library to the machinery based on the interface of Gaussian and Tinker to perform QM/AMOEBA molecular dynamics. As an application, we study the excited state intramolecular proton transfer of 3-hydroxyflavone in two solvents: methanol and methylcyclohexane. By using a combination of molecular dynamics and umbrella sampling, we find an ultrafast component of the transfer, which is common to the two solvents, and a much slower component, which is active in the protic solvent only. The mechanisms of the two components are explained in terms of intramolecular vibrational redistribution and intermolecular hydrogen-bonding, respectively. Ground and excited state free energies along an effective reaction coordinate are finally obtained allowing for a detailed analysis of the solvent mediated mechanism.
Nottoli, M., Cupellini, L., Lipparini, F., Granucci, G., Mennucci, B.
Multiscale Models for Light-Driven Processes
Annual Review of Physical Chemistry 72, 489-513 (2021).  <Read>
Multiscale models combining quantum mechanical and classical descriptions are a very popular strategy to simulate properties and processes of complex systems. Many alternative formulations have been developed, and they are now available in all of the most widely used quantum chemistry packages. Their application to the study of light-driven processes, however, is more recent, and some methodological and numerical problems have yet to be solved. This is especially the case for the polarizable formulation of these models, the recent advances in which we review here. Specifically, we identify and describe the most important specificities that the polarizable formulation introduces into both the simulation of excited-state dynamics and the modeling of excitation energy and electron transfer processes.
Cardoso Ramos, F., Cupellini, L., Mennucci, B.
Computational Investigation of Structural and Spectroscopic Properties of LOV-Based Proteins with Improved Fluorescence.
J. Phys. Chem. B 125, 1768–1777 (2021). <Read>
Abstract: Flavin-based fluorescent proteins are a class of fluorescent reporters derived from light, oxygen, and voltage (LOV) sensing proteins. Through mutagenesis, natural LOV proteins have been engineered to obtain improved fluorescence properties. In this study, we combined extended classical Molecular Dynamics simulations and multiscale Quantum Mechanics/Molecular Mechanics methods to clarify the relationship between structural and dynamic changes induced by specific mutations and the spectroscopic response. To reach this goal we compared two LOV variants, one obtained by the single mutation needed to photochemically inactivate the natural system, and the other (iLOV) obtained through additional mutations and characterized by a significantly improved fluorescence. Our simulations confirmed the “flipping and crowding” effect induced in iLOV by the additional mutations and revealed its mechanism of action. We also showed that these mutations, and the resulting differences in the composition and flexibility of the binding pockets, are not reflected in significant shifts of the excitation and emission energies, in agreement with the similarity of the spectra measured for the two systems. However, a small but consistent reduction was found in the Stokes shift of iLOV, suggesting a reduction of the intermolecular reorganization experienced by the chromophore after excitation, which could slow down its internal conversion to the ground state and improve the fluorescence.
Macaluso, V., Salvadori, G., Cupellini, L., Mennucci, B.
The structural changes in the signaling mechanism of bacteriophytochromes in solution revealed by a multiscale computational investigation.
Chem. Sci. 12, 5555-5565 (2021).  <Read>
Abstract: Phytochromes are red-light sensing proteins, with important light-regulatory roles in different organisms, which are capturing an increasing interest in bioimaging and optogenetics. Upon absorption of light by the embedded bilin chromophore, they undergo structural changes that extend from the chromophore to the protein and finally drive the biological function. Up to now, the underlying mechanism still has to be characterized fully. Here we investigate the Pfr activated form of a bacterial phytochrome, by combining extensive molecular dynamics simulations with a polarizable QM/MM description of the spectroscopic properties, revealing a large structure relaxation in solution, compared to the crystal structure, both in the chromophore-binding pocket and in the overall structure of the phytochrome. Our results indicate that the final opening of the dimeric structure is preceded by an important internal reorganization of the phytochrome specific (PHY) domain involving a bend of the helical spine connecting the PHY domain with the chromophore-binding domain, opening the way to a new understanding of the activation pathway.
Mascoli, V. , Liguori, N., Cupellini, L., Mennucci, B., Croce, R.
Uncovering the interactions driving carotenoid binding in light-harvesting complexes.
Chem, Sci, 12, 5113-5122 (2021). <Read>
Carotenoids are essential constituents of plant light-harvesting complexes (LHCs), being involved in protein stability, light harvesting, and photoprotection. Unlike chlorophylls, whose binding to LHCs is known to require coordination of the central magnesium, carotenoid binding relies on weaker intermolecular interactions (such as hydrogen bonds and van der Waals forces), whose character is far more elusive. Here we addressed the key interactions responsible for carotenoid binding to LHCs by combining molecular dynamics simulations and polarizable quantum mechanics/molecular mechanics calculations on the major LHC, LHCII. We found that carotenoid binding is mainly stabilized by van der Waals interactions with the surrounding chlorophyll macrocycles rather than by hydrogen bonds to the protein, the latter being more labile than predicted from structural data. Furthermore, the interaction network in the binding pockets is relatively insensitive to the chemical structure of the embedded carotenoid. Our results are consistent with a number of experimental data and challenge the role played by specific interactions in the assembly of pigment-protein complexes.
Guido, C. A., Chrayteh, A., Scalmani, G., Mennucci, B., Jacquemin, D.
Simple Protocol for Capturing Both Linear-Response and State-Specific Effects in Excited-State Calculations with Continuum Solvation Models. 
J Chem Theory Comput 17, 5155–5164 (2021). <Read>
Simple Protocol for Capturing Both Linear-Response and State-Specific Effects in Excited-State Calculations with Continuum Solvation Models We present an effective computational protocol (cLR2) to describe both solvatochromism and fluorosolvatochromism. This protocol, which couples the polarizable continuum model to time-dependent density functional theory, simultaneously accounts for both linear-response and state-specific solvation effects. A series of test cases, including solvatochromic and fluorosolvatochromic compounds and excited-state intramolecular proton transfers, are used to highlight that cLR2 is especially beneficial for modeling bright excitations possessing a significant charge-transfer character, as well as cases in which an accurate balance between states of various polarities should be restored.


Lapillo, M., Cignoni, E., Cupellini, L. & Mennucci, B.
The energy transfer model of nonphotochemical quenching_ Lessons from the minor CP29 antenna complex of plants.
BBA - Bioenergetics 1861, 148282 (2020). <Read>
Abstract: Antenna complexes in photosystems of plants and green algae are able to switch between a light-harvesting unquenched conformation and a quenched conformation so to avoid photodamage. When the switch is activated, nonphotochemical quenching (NPQ) mechanisms take place for an efficient deactivation of excess excitation energy. The molecular details of these mechanisms have not been fully clarified but different hypotheses have been proposed. Among them, a popular one involves excitation energy transfer (EET) from the singlet excited Chls to the lowest singlet state (S1) of carotenoids. In this work, we combine such model with μs-long molecular dynamics simulations of the CP29 minor antenna complex to investigate how conformational fluctuations affect the electronic couplings and the final EET quenching. The computational framework is applied to both CP29 embedding violaxanthin and zeaxantin in its L2 site. Our results demonstrate that the EET model is rather insensitive to physically reasonable variations in single chlorophyll-carotenoid couplings, and that very large conformational changes would be needed to see the large variation of the complex lifetime expected in the switch from light-harvesting to quenched state. We show, however, that a major role in regulating the EET quenching is played by the S1 energy of the carotenoid, in line with very recent spectroscopy experiments.

Nottoli, M., Mennucci, B. & Lipparini, F.
Excited state Born-Oppenheimer molecular dynamics through coupling between time dependent DFT and AMOEBA.
Phys Chem Chem Phys 22, 19532–19541 (2020). <Read>
Abstract: We present the implementation of excited state Born–Oppenheimer molecular dynamics (BOMD) using a polarizable QM/MM approach based on a time-dependent density functional theory (TDDFT) formulation and the AMOEBA force field. The implementation relies on an interface between Tinker and Gaussian software and it uses an algorithm for the calculation of QM/MM energy and forces which scales linearly with the number of MM atoms. The resulting code can perform TDDFT/AMOEBA BOMD simulations on real-life systems with standard computational resources. As a test case, the method is applied to the study of the mechanism of locally-excited to charge-transfer conversion in dimethylaminobenzonitrile in a polar solvent. Our simulations confirm that such a conversion is governed by the twisting of the dimethylamino group which is accompanied by an important reorientation of solvent molecules.

Persano, L., Szukalski, A., Gaio, M., Moffa, M., Salvadori, G., Sznitko, L., Camposeo, A., Mysliwiec, J., Sapienza, R., Mennucci, B., Pisignano, D.
Dye Stabilization and Wavelength Tunability in Lasing Fibers Based on DNA.
Adv. Optical Mater. 20, 2001039–8 (2020). <Read>
Abstract: Lasers based on biological materials are attracting an increasing interest in view of their use in integrated and transient photonics. Deoxyribonucleic acid (DNA) as optical biopolymer in combination with highly emissive dyes has been reported to have excellent potential in this respect. However, achieving miniaturized lasing systems based on solid‐state DNA shaped in different geometries to confine and enhance emission is still a challenge, and the physicochemical mechanisms originating fluorescence enhancement are not fully understood. Herein, a class of wavelength‐tunable lasers based on DNA nanofibers is demonstrated, for which optical properties are highly controlled through the system morphology. A synergistic effect is highlighted at the basis of lasing action. Through a quantum chemical investigation, it is shown that the interaction of DNA with the encapsulated dye leads to hindered twisting and suppressed channels for the nonradiative decay. This is combined with effective waveguiding, optical gain, and tailored mode confinement to promote morphologically controlled lasing in DNA‐based nanofibers. The results establish design rules for the development of bright and tunable nanolasers and optical networks based on DNA nanostructures.

Cupellini, L., Lipparini, F. & Cao, J.
Absorption and Circular Dichroism Spectra of Molecular Aggregates With the Full Cumulant Expansion.
J. Phys. Chem. B 124, 8610–8617 (2020). <Read>
Abstract: The exciton Hamiltonian of multichromophoric aggregates can be probed by spectroscopic techniques such as linear absorption and circular dichroism. To compare calculated Hamiltonians to experiments, a lineshape theory is needed, which takes into account the coupling of the excitons with inter- and intramolecular vibrations. This coupling is normally introduced in a perturbative way through the cumulant expansion formalism and further approximated by assuming a Markovian exciton dynamics, for example with the modified Redfield theory. Here, we present the implementation of the full cumulant expansion (FCE) formalism ( J. Chem. Phys. 142, 2015, 094106) to efficiently compute absorption and circular dichroism spectra of molecular aggregates beyond the Markov approximation, without restrictions on the form of exciton–phonon coupling. By employing the LH2 system of purple bacteria as a challenging test case, we compare the FCE lineshapes with the Markovian lineshapes obtained with the modified Redfield theory, showing that the latter presents a less satisfying agreement with experiments. The FCE approach instead accurately describes the lineshapes, especially in the vibronic sideband of the B800 peak. We envision that the FCE approach will become a valuable tool for accurately comparing model exciton Hamiltonians with optical spectroscopy experiments.

Bondanza, M., Cupellini, L., Faccioli, P. & Mennucci, B.
Molecular Mechanisms of Activation in the Orange Carotenoid Protein Revealed by Molecular Dynamics.
J. Am. Chem. Soc. 142, 21829–21841 (2020)  <Read>
Light-harvesting in photosynthesis is accompanied by photoprotective processes. In cyanobacteria, the photoprotective role is played by a specialized complex, the orange carotenoid protein, which is activated by strong blue-green light. This photoactivation involves a unique series of structural changes which terminate with an opening of the complex into two separate domains, one of which acts as a quencher for the light-harvesting complexes. Many experimental studies have tried to reveal the molecular mechanisms through which the energy absorbed by the carotenoid finally leads to the large conformational change of the complex. Here, for the first time, these mechanisms are revealed by simulating at the atomistic level the whole dynamics of the complex through an effective combination of enhanced sampling techniques. On the basis of our findings, we can conclude that the carotenoid does not act as a spring that, releasing its internal strain, induces the dissociation, as was previously proposed, but as a “latch” locking together the two domains. The photochemically triggered displacement of the carotenoid breaks this balance, allowing the complex to dissociate.

Bondanza, M., Nottoli, M., Cupellini, L., Lipparini, F. & Mennucci, B.
Polarizable embedding QM/MM: the future gold standard for complex (bio)systems?
Phys Chem Chem Phys 22, 14433–14448 (2020)  <Read>
Nowadays, hybrid QM/MM approaches are widely used to study (supra)molecular systems embedded in complex biological matrices. However, in their common formulation, mutual interactions between the quantum and classical parts are neglected. To go beyond such a picture, a polarizable embedding can be used. In this perspective, we focus on the induced point dipole formulation of polarizable QM/MM approaches and we show how efficient and linear scaling implementations have allowed their application to the modeling of complex biosystems. In particular, we discuss their use in the prediction of spectroscopies and in molecular dynamics simulations, including Born–Oppenheimer dynamics, enhanced sampling techniques and nonadiabatic descriptions. We finally suggest the theoretical and computational developments that still need to be achieved to overcome the limitations which have prevented so far larger diffusion of these methods.

Sláma, V., Cupellini, L. & Mennucci, B.
Exciton properties and optical spectra of light harvesting complex II from a fully atomistic description.
Physical Chemistry Chemical Physics 10, 492–13 (2020)  <Read>
We present a fully atomistic simulation of linear optical spectra (absorption, fluorescence and circular dichroism) of the Light Harvesting Complex II (LHCII) trimer using a hybrid approach, which couples a quantum chemical description of the chlorophylls with a classical model for the protein and the external environment (membrane and water). The classical model uses a polarizable Molecular Mechanics force field, thus allowing mutual polarization effects in the calculations of the excitonic properties. The investigation is performed both on the crystal structure and on structures generated by a μs long classical molecular dynamics simulation of the complex within a solvated membrane. The results show that this integrated approach not only provides a good description of the excitonic properties and optical spectra without the need for additional refinements of the excitonic parameters, but it also allows an atomistic investigation of the relative importance of electronic, structural and environment effects in determining the optical spectra.

S. Hashem, L. Cupellini, F. Lipparini, and B. Mennucci
A polarisable QM/MM description of NMR chemical shifts of a photoreceptor protein.
Molecular Physics, 2020 vol. 0 (0) pp. 1-10  <Read>
We present a polarisable QM/MM investigation of NMR chemical shifts of a photoreceptor protein belonging to the Blue Light-Using Flavin family. Two different structures have been proposed for this photoreceptor which show a large variability in terms of the position and orientation of the protein residues around the flavin chromophore. Here, the two structures have been investigated with our multiscale approach using both DFT and MP2 level of theory. The picture that comes out compar- ing the 1H chemical shifts of the flavin and the most strongly interacting protein residues with the available experimental data, indicates a different behaviour of the two structures, with one showing a better correlation with NMR measurements. This shows that hybrid quantum chemical-classical simulations of NMR chemical shifts can indeed become a valuable tool to investigate the structure of complex biosystems.

L. Cupellini, M. Bondanza, M. Nottoli, and B. Mennucci,
Successes & challenges in the atomistic modeling of light-harvesting and its photoregulation.
BBA - Bioenergetics, 2020 vol. 1861 (4) p. 148049  <Read>
Light-harvesting is a crucial step of photosynthesis. Its mechanisms and related energetics have been revealed by a combination of experimental investigations and theoretical modeling. The success of theoretical modeling is largely due to the application of atomistic descriptions combining quantum chemistry, classical models and molecular dynamics techniques. Besides the important achievements obtained so far, a complete and quantitative understanding of how the many different light- harvesting complexes exploit their structural specificity is still missing. Moreover, many questions remain unanswered regarding the mechanisms through which light-harvesting is regulated in response to variable light conditions. Here we show that, in both fields, a major role will be played once more by atomistic descriptions, possibly generalized to tackle the numerous time and space scales on which the regulation takes place: going from the ultrafast electronic excitation of the multichromophoric aggregate, through the subsequent conformational changes in the embedding protein, up to the interaction between proteins.

V. Macaluso, L. Cupellini, G. Salvadori, F. Lipparini, and B. Mennucci,
Elucidating the role of structural fluctuations, and intermolecular and vibronic interactions in the spectroscopic response of a bacteriophytochrome.
Phys Chem Chem Phys, 2020 vol. 22 (16) pp. 8585-8594  <Read>
We present the first comprehensive multiscale computational investigation of Resonance Raman, absorption and Circular Dichroism spectra of the resting state of the Deinococcus radiodurans phytochrome. The spectra are simulated in all their components, namely the energy position and the lineshapes of both the far-red and the blue bands. To achieve such a goal, we have combined a 4.5 ms MD simulation of the solvated dimeric phytochrome with a hybrid quantum mechanics/molecular mechanics (QM/MM) model, which accounts for both electrostatic and mutual polarization effects between the QM and the MM subsystems. A good agreement with experiments is found for all the three spectra. Moreover, we find a transient H-bond network within the binding pocket of the biliverdin chromophore that, unexpectedly, does not significantly affect the spectra. In parallel, we characterize the vibrations that are more strongly coupled to the biliverdin excitation, confirming the important role of the hydrogen-out-of-plane mode of its vinyl C–H together with the expected C=C stretching of the double bond involved in the photoisomerization.

L. Cupellini, D. Calvani, D. Jacquemin, B. Mennucci,
Charge transfer from the carotenoid can quench chlorophyll excitation in antenna complexes of plants.
Nature Communications , 2020 , vol. 11 , p. 662  <Read>
The photosynthetic apparatus of higher plants can dissipate excess excitation energy during high light exposure, by deactivating excited chlorophylls through a mechanism called nonphotochemical quenching (NPQ) However, the precise molecular details of quenching and the mechanism regulating the quenching level are still not completely understood Focusing on the major light-harvesting complex LHCII of Photosystem II, we show that a charge transfer state involving Lutein can efficiently quench chlorophyll excitation, and reduce the excitation lifetime of LHCII to the levels measured in the deeply quenched LHCII aggregates Through a combination of molecular dynamics simulations, multiscale quantum chemical calculations, and kinetic modeling, we demonstrate that the quenching level can be finely tuned by the protein, by regulating the energy of the charge transfer state Our results suggest that a limited conformational rearrangement of the protein scaffold could act as a molecular switch to activate or deactivate the quenching mechanism

M. Bondanza, L. Cupellini, F. Lipparini, B. Mennucci,

The Multiple Roles of the Protein in the Photoactivation of Orange Carotenoid Protein.
Chem , 2020 , vol. 6 , p. 187 - 203  <Read>
Orange carotenoid protein (OCP) is a carotenoid-binding protein involved in photo-protection mechanisms of cyanobacteria Upon exposure to high light, OCP interconverts from an orange resting form (OCPO) to a red active one (OCPR); the mechanism of this interconversion, even if extensively studied, has still not been fully elucidated In this work, we use multiscale atomistic models ranging from classical to hybrid quantum-classical (QM/MM) molecular dynamics to give a comprehensive molecular explanation of the drastic spectroscopic changes observed upon interconversion The findings are finally used to formulate a new hypothesis on the role of the protein in the photoactivation mechanism.



F. Cardoso ramos, M. Nottoli, L. Cupellini, B. Mennucci,
The molecular mechanisms of light adaption in light-harvesting complexes of purple bacteria revealed by a multiscale modeling.
Chem. Sci. , 2019, vol. 2, 315-330  <Read>
The light-harvesting in photosynthetic purple bacteria can be tuned in response to the light conditions during cell growth One of the used strategies is to change the energy of the excitons in the major fight-harvesting complex, commonly known as LH2 In the present study we report the first systematic investigation of the microscopic origin of the exciton tuning using three complexes, namely the common (high-light) and the low-light forms of LH2 from Rps acidophila plus a third complex analogous to the PucD complex from Rps palustris The study is based on the combination of classical molecular dynamics of each complex in a lipid membrane and excitonic calculations based on a multiscale quantum mechanics/molecular mechanics approach including a polarizable embedding From the comparative analysis, it comes out that the mechanisms that govern the adaptation of the complex to different light conditions use the different H-bonding environment around the bacteriochlorophyll pigments to dynamically control both internal and inter-pigment degrees of freedom While the former have a large effect on the site energies, the latter significantly change the electronic couplings, but only the combination of the two effects can fully reproduce the tuning of the final excitons and explain the observed spectroscopic differences

R. Nifosì, B. Mennucci, C. Filippi,
The key to the yellow-to-cyan tuning in the green fluorescent protein family is polarisation.
Phys. Chem. Chem. Phys.Phys. , 2019, vol. 21, p. 18988-18998  <Read>
Computational approaches have to date failed to fully capture the large (about 0 4 eV) excitation energy tuning displayed by the nearly identical anionic chromophore in different green fluorescent protein (GFP) variants Here, we present a thorough comparative study of a set of proteins in this sub-family, including the most red- (phiYFP) and blue-shifted (mTFP0 7) ones We employ a classical polarisable embedding through induced dipoles and combine it with time-dependent density functional theory and multireference perturbation theory in order to capture both state-specific induction contributions and the coupling of the polarisation of the protein to the chromophore transition density The obtained results show that only upon inclusion of both these two effects generated by the mutual polarisation between the chromophore and the protein can the full spectral tuning be replicated We finally discuss how this mutual polarisation affects the correlation between excitation energies, dipole moment variation, and molecular electrostatic field

L. Cupellini, M. Bondanza, M. Nottoli, B. Mennucci,
Successes & challenges in the atomistic modeling of light-harvesting and its photoregulation.
BBA - Bioenergetics , 2019 , p. 148049  <Read>
Light-harvesting is a crucial step of photosynthesis Its mechanisms and related energetics have been revealed by a combination of experimental investigations and theoretical modeling The success of theoretical modeling is largely due to the application of atomistic descriptions combining quantum chemistry, classical models and molecular dynamics techniques Besides the important achievements obtained so far, a complete and quantitative understanding of how the many different light-harvesting complexes exploit their structural specificity is still missing Moreover, many questions remain unanswered regarding the mechanisms through which light-harvesting is regulated in response to variable light conditions Here we show that, in both fields, a major role will be played once more by atomistic descriptions, possibly generalized to tackle the numerous time and space scales on which the regulation takes place: going from the ultrafast electronic excitation of the multichromophoric aggregate, through the subsequent conformational changes in the embedding protein, up to the interaction between proteins

F. Segatta, L. Cupellini, M. Garavelli, B. Mennucci,
Quantum Chemical Modeling of the Photoinduced Activity of Multichromophoric Biosystems.
Chem. Rev. , 2019 , vol. 119 , p. 9361-9380  <Read>
Multichromophoric biosystems represent a broad family with very diverse members, ranging from light-harvesting pigment–protein complexes to nucleic acids The former are designed to capture, harvest, efficiently transport, and transform energy from sunlight for photosynthesis, while the latter should dissipate the absorbed radiation as quickly as possible to prevent photodamages and corruption of the carried genetic information Because of the unique electronic and structural characteristics, the modeling of their photoinduced activity is a real challenge Numerous approaches have been devised building on the theoretical development achieved for single chromophores and on model Hamiltonians that capture the essential features of the system Still, a question remains: is a general strategy for the accurate modeling of multichromophoric systems possible? By using a quantum chemical point of view, here we review the advancements developed so far highlighting differences and similarities with the single chromophore treatment Finally, we outline the important limitations and challenges that still need to be tackled to reach a complete and accurate picture of their photoinduced properties and dynamics

D. Loco, L. Lagardère, G. A. Cisneros, G. Scalmani, M. Frisch, F. Lipparini, B. Mennucci, J. Piquemal,
Towards large scale hybrid QM/MM dynamics of complex systems with advanced point dipole polarizable embeddings.
Chem. Sci. , 2019 , vol. 10 , p. 7200-7211  <Read>
In this work, we present a general route to hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) Molecular Dynamics for complex systems using a polarizable embedding We extend the capabilities of our hybrid framework, combining the Gaussian and Tinker/Tinker-HP packages in the context of the AMOEBA polarizable force field to treat large (bio)systems where the QM and the MM subsystems are covalently bound, adopting pseudopotentials at the boundaries between the two regions We discuss in detail the implementation and demonstrate the global energy conservation of our QM/MM Born–Oppenheimer molecular dynamics approach using Density Functional Theory Finally, the approach is assessed on the electronic absorption properties of a 16 500 atom complex encompassing an organic dye embedded in a DNA matrix in solution, extending the hybrid method to a time-dependent Density Functional Theory approach The results obtained comparing different partitions between the quantum and the classical subsystems also suggest that large QM portions are not necessary if accurate polarizable force fields are used in a variational formulation of the embedding, properly including the QM/MM mutual polarization

B. Mennucci, S. Corni
Multiscale modelling of photoinduced processes in composite systems.
Nat. Rev. Chem. , 2019 , vol. 3 , p. 315-330  <Read>
In the past few decades, quantum mechanical (QM) modelling has moved from isolated molecules made of few atoms to large supramolecular aggregates embedded in complex environments The integration of QM methods within classical descriptions in multiscale models made such advances possible One of the first examples of this integration is represented by continuum solvation models that have been largely and successfully applied to predict properties and processes of solvated molecules since the 1980s Almost in the same years, an alternative classical description based on molecular mechanics (MM) was coupled to QM methods in hybrid QM/MM approaches Since their first formulations, these QM/classical models have seen great development in terms of accuracy, robustness and generalizability This progress has enabled their application to systems of increasing complexity and processes never studied before within a QM framework, such as photoinduced processes in biomolecules, nanomaterials and, more generally, composite systems These systems bring together components of different sizes — molecular, nano and mesoscopic — and multiscale approaches enable their simultaneous investigation In this Review, we highlight potentials and limitations of multiscale approaches for the modelling of photoinduced processes in composite systems We discuss the developments that are still needed to elevate the QM-based multiscale strategy to a gold standard for the prediction of light-activated events in composite systems and the analysis of the outputs of novel advanced spectroscopies.

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This project has received funding from the European Research Council (ERC) 
under the Horizon 2020 research and innovation programme
(Grant agreement No. 786714)