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Various approaches have been proposed to include the effect of pH in molecular dynamics (MD) simulations. Among these, the λ-dynamics approach proposed by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys.1996, 105, 2414−2423] can be performed with little computational overhead and hfor each typeence be used to routinely perform MD simulations at microsecond time scales, as shown in the accompanying paper [Aho, N. et al. J. Chem. Theory Comput.2022, DOI: 10.1021/acs.jctc.2c00516]. At such time scales, however, the accuracy of the molecular mechanics force field and the parametrization becomes critical. Here, we address these issues and provide the community with guidelines on how to set up and perform long time scale constant pH MD simulations. We found that barriers associated with the torsions of side chains in the CHARMM36m force field are too high for reaching convergence in constant pH MD simulations on microsecond time scales. To avoid the high computational cost of extending the sampling, we propose small modifications to the force field to selectively reduce the torsional barriers. We demonstrate that with such modifications we obtain converged distributions of both protonation and torsional degrees of freedom and hence consistent pKa estimates, while the sampling of the overall configurational space accessible to proteins is unaffected as compared to normal MD simulations. We also show that the results of constant pH MD depend on the accuracy of the correction potentials. While these potentials are typically obtained by fitting a low-order polynomial to calculated free energy profiles, we find that higher order fits are essential to provide accurate and consistent results. By resolving problems in accuracy and sampling, the work described in this and the accompanying paper paves the way to the widespread application of constant pH MD beyond pKa prediction. peerReviewed

Molecular dynamics (MD) simulations are routinely performed of biomolecules in solution, because this is their native environment. However, the structures used in such simulations are often obtained with x-ray crystallography, which provides the atomic coordinates of the biomolecule in a crystal environment. With the advent of free electron lasers, x-ray crystallography can also access the dynamics in crystals. Such experiments provide the possibility to directly verify the validity of an MD simulation. A direct comparison requires that the simulation of the biomolecule is also performed in the crystal environment. However, in contrast to simulations of biomolecules in solution, setting up a crystal is challenging. In particular, because not all solvent molecules are resolved in x-ray crystallography, adding an appropriate number of solvent molecules can be difficult and typically is a trial-and-error based procedure requiring manual interventions. Such interventions preclude high throughput applications. To overcome this bottleneck, we introduce gmXtal, a tool for setting up crystal simulations for MD simulations with GROMACS. With the information from the protein data bank rcsb.org gmXtal automatically (i) builds the unit cell; (ii) sets the protonation of titratable residues; (iii) builds missing residues that were not resolved experimentally; and (iv) adds an appropriate number of solvent molecules to the system. gmXtal is available as a standalone tool https://gitlab.com/pbuslaev/gmxtal.

Transfer of excitation energy is a key step in light harvesting and hence of technological relevance for solar energy conversion. In bare organic materials energy transfer proceeds via incoherent hops, which restrict propagation lengths to nanometers. In contrast, energy transport over several micrometers has been observed in the strong coupling regime where excitations hybridise with confined light modes to form polaritons. Because polaritons have group velocity, their propagation should be ballistic and long-ranged. However, experiments indicate that organic polaritons propagate in a diffusive manner and more slowly than their group velocity. Here, we resolve this controversy by means of molecular dynamics simulations of Rhodamine molecules in a Fabry-Pérot cavity. Our results suggest that polariton propagation is limited by the cavity lifetime and appears diffusive due to reversible population transfers between bright polaritonic states that propagate ballistically at their group velocity, and dark states that are stationary. Furthermore, because long-lived dark states transiently trap the excitation, propagation is observed on timescales beyond the intrinsic polariton lifetime. These atomistic insights not only help to better understand and interpret experimental observations, but also pave the way towards rational design of molecule-cavity systems for achieving long-range coherent energy transport.

Exciton transport in most organic materials is based on an incoherent hopping process between neighboring molecules. This process is very slow, setting a limit to the performance of organic optoelectronic devices. In this Article, we overcome the incoherent exciton transport by strongly coupling localized singlet excitations in a tetracene crystal to confined light modes in an array of plasmonic nanoparticles. We image the transport of the resulting exciton–polaritons in Fourier space at various distances from the excitation to directly probe their propagation length as a function of the exciton to photon fraction. Exciton–polaritons with an exciton fraction of 50% show a propagation length of 4.4 μm, which is an increase by 2 orders of magnitude compared to the singlet exciton diffusion length. This remarkable increase has been qualitatively confirmed with both finite-difference time-domain simulations and atomistic multiscale molecular dynamics simulations. Furthermore, we observe that the propagation length is modified when the dipole moment of the exciton transition is either parallel or perpendicular to the cavity field, which opens a new avenue for controlling the anisotropy of the exciton flow in organic crystals. The enhanced exciton–polariton transport reported here may contribute to the development of organic devices with lower recombination losses and improved performance. peerReviewed

Photoactivation of bacteriophytochrome involves a cis–trans photoisomerization of a biliverdin chromophore, but neither the precise sequence of events nor the direction of the isomerization is known. Here, we used nonadiabatic molecular dynamics simulations on the photosensory protein dimer to resolve the isomerization mechanism in atomic detail. In our simulations the photoisomerization of the D ring occurs in the counterclockwise direction. On a subpicosecond time scale, the photoexcited chromophore adopts a short-lived intermediate with a highly twisted configuration stabilized by an extended hydrogen-bonding network. Within tens of picoseconds, these hydrogen bonds break, allowing the chromophore to adopt a more planar configuration, which we assign to the early Lumi-R state. The isomerization process is completed via helix inversion of the biliverdin chromophore to form the late Lumi-R state. The mechanistic insights into the photoisomerization process are essential to understand how bacteriophytochrome has evolved to mediate photoactivation and to engineer this protein for new applications. peerReviewed

Interactions between an atomically precise gold nanocluster Au102(p-MBA)44 (p-MBA = para mercaptobenzoic acid) and a fluorescent organic dye molecule (KU, azadioxatriangulenium) are studied. In solution, the constituents form spontaneously a weakly bound complex leading to quenching of fluorescence of the KU dye via energy transfer. The KU can be separated from the complex by lowering pH, leading to recovery of fluorescence, which forms a basis for an optical reversible pH sensor. However, the sensor is not a stable entity, which could be delivered inside cells. For this purpose, a covalently bound hybrid is synthesized by linking the KU dye to the ligand layer of the cluster via an ester bond. Covalent linking facilitates entry of the cluster–dye hybrids into cells via endocytosis. Inside cells, the hybrids accumulate in endosomes where Au102 releases its cargo via hydrolysis of the ester bond. Changes of the local pH inside endosomes regulate reversible fluorescence due to variations in the interactions between the Au102 cluster and the dye. This work presents a concept for delivering reporter molecules into cells by using atomically precise gold nanoclusters as carriers and paves the way for future developments of cluster-reporter sensors for in vivo measurements of e.g. absolute pH values or ion concentrations.

Photoactivation in the Photoactive Yellow Protein, a bacterial blue light photoreceptor, proceeds via photo-isomerization of the double C=C bond in the covalently attached chromophore. Quantum chemistry calculations, however, have suggested that in addition to double bond photo-isomerization, the isolated chromophore and many of its analogues, can isomerize around a single C-C bond as well. Whereas double bond photo-isomerization has been observed with x-ray crystallography, experimental evidence for single bond photo-isomerization is currently lacking. Therefore, we have synthesized a chromophore analogue, in which the formal double bond is covalently locked in a cyclopentenone ring and carried out transient absorption spectroscopy experiments in combination with non-adiabatic molecular dynamics simulations to reveal that the locked chromophore isomerizes around the single bond upon photo-activation. Our work thus provides experimental evidence for single bond photo-isomerization in a photoactive yellow protein chromophore analogue and suggests that photo-isomerization is not restricted to the double bonds in conjugated systems. This insight may be useful for designing light-driven molecular switches or motors. peerReviewed

The cellular energy machinery crucially depends on the transmembrane proton po- tential difference (protonmotive force). Here we show that the presence of sodium ions at physiological salt concentrations reduces the proton’s affinity for the mem- brane surface, and introduces a thermodynamic barrier between bulk and surface. In contrast, potasium ions have no effect. The different sodium concentrations within distinct cellular compartments lead to an asymmetric transmembrane proton free- energy profile. We discuss the effect this asymmetry might have on theprotonmotive forceat rest and under respiratory steady-state condition.

Aptamer selection against novel infections is a complicated and time-consuming approach. Synergy can be achieved by using computational methods together with experimental procedures. This study aims to develop a reliable methodology for a rational aptamer in silico et vitro design. The new approach combines multiple steps: (1) Molecular design, based on screening in a DNA aptamer library and directed mutagenesis to fit the protein tertiary structure; (2) 3D molecular modeling of the target; (3) Molecular docking of an aptamer with the protein; (4) Molecular dynamics (MD) simulations of the complexes; (5) Quantum-mechanical (QM) evaluation of the interactions between aptamer and target with further analysis; (6) Experimental verification at each cycle for structure and binding affinity by using small-angle X-ray scattering, cytometry, and fluorescence polarization. By using a new iterative design procedure, structure- and interaction-based drug design (SIBDD), a highly specific aptamer to the receptor-binding domain of the SARS-CoV-2 spike protein, was developed and validated. The SIBDD approach enhances speed of the high-affinity aptamers development from scratch, using a target protein structure. The method could be used to improve existing aptamers for stronger binding. This approach brings to an advanced level the development of novel affinity probes, functional nucleic acids. It offers a blueprint for the straightforward design of targeting molecules for new pathogen agents and emerging variants.

The strong light–matter coupling regime, in which excitations of materials hybridize with excitations of confined light modes into polaritons, holds great promise in various areas of science and technology. A key aspect for all applications of polaritonic chemistry is the relaxation into the lower polaritonic states. Polariton relaxation is speculated to involve two separate processes: vibrationally assisted scattering (VAS) and radiative pumping (RP), but the driving forces underlying these two mechanisms are not fully understood. To provide mechanistic insights, we performed multiscale molecular dynamics simulations of tetracene molecules strongly coupled to the confined light modes of an optical cavity. The results suggest that both mechanisms are driven by the same molecular vibrations that induce relaxation through nonadiabatic coupling between dark states and polaritonic states. Identifying these vibrational modes provides a rationale for enhanced relaxation into the lower polariton when the cavity detuning is resonant with specific vibrational transitions. peerReviewed

When photoactive molecules interact strongly with confined light modes in optical cavities, new hybrid light–matter states form. They are known as polaritons and correspond to coherent superpositions of excitations of the molecules and of the cavity photon. The polariton energies and thus potential energy surfaces are changed with respect to the bare molecules, such that polariton formation is considered a promising paradigm for controlling photochemical reactions. To effectively manipulate photochemistry with confined light, the molecules need to remain in the polaritonic state long enough for the reaction on the modified potential energy surface to take place. To understand what determines this lifetime, we have performed atomistic molecular dynamics simulations of room-temperature ensembles of rhodamine chromophores strongly coupled to a single confined light mode with a 15 fs lifetime. We investigated three popular experimental scenarios and followed the relaxation after optically pumping (i) the lower polariton, (ii) the upper polariton, or (iii) uncoupled molecular states. The results of the simulations suggest that the lifetimes of the optically accessible lower and upper polaritons are limited by (i) ultrafast photoemission due to the low cavity lifetime and (ii) reversible population transfer into the “dark” state manifold. Dark states are superpositions of molecular excitations but with much smaller contributions from the cavity photon, decreasing their emission rates and hence increasing their lifetimes. We find that population transfer between polaritonic modes and dark states is determined by the overlap between the polaritonic and molecular absorption spectra. Importantly, excitation can also be transferred ”upward” from the lower polariton into the dark-state reservoir due to the broad absorption spectra of the chromophores, contrary to the common conception of these processes as a ”one-way” relaxation from the dark states down to the lower polariton. Our results thus suggest that polaritonic chemistry relying on modified dynamics taking place within the lower polariton manifold requires cavities with sufficiently long lifetimes and, at the same time, strong light–matter coupling strengths to prevent the back-transfer of excitation into the dark states, This work was supported by the Academy of Finland (Grants 289947 to JJT, 290677 to GG, and 285481 to DM) as well as the European Research Council (ERC-2016-StG-714870 to JF) and the Spanish Ministry for Science, Innovation, and Universities − AEI (RTI2018-099737-B-I00 to JF). We thank the Center for Scientific Computing (CSC-IT Center for Science) for computational resources and Fredrik Robertsen in particular ́ for his help with running our simulations on GPUs. We also acknowledge PRACE for awarding us access to resource Curie based in France at GENCI

The tetrapyrrole chromophore biliverdin IXα (BV) in the bacteriophytochrome from Deinococcus radiodurans (DrBphP) is usually assumed to be fully protonated, but this assumption has not been systematically validated by experiments or extensive computations. Here, we use force field molecular dynamics simulations and quantum mechanics/molecular mechanics calculations with density functional theory and XMCQDPT2 methods to investigate the effect of the five most probable protonation forms of BV on structural stability, binding pocket interactions, and absorption spectra in the two photochromic states of DrBphP. While agreement with X-ray structural data and measured UV/vis spectra suggest that in both states the protonated form of the chromophore dominates, we also find that a minor population with a deprotonated D-ring could contribute to the red-shifted tail in the absorption spectra.

Part of theBioExcel Virtual Workshop on Best Practices in QM/MM Simulation of Biomolecular Systems Video recording available at https://www.youtube.com/watch?v=iF05I-r6YW8 Abstract The BioExcel Virtual Workshop on Best Practices in QM/MM Simulation of Biomolecular Systems featured talks by invited speakers on a range of topics. Recordings and slides of these webinars are available via the workshop overview page linked above, and directly on our YouTube channel. On Friday January 29th the workshop culminated in a final panel session in which all the invited speakers joined to discuss important challenges and corresponding best practices regarding the use of QM/MM approaches for biomolecular modelling and simulation. The panel reflected on and shared views on recurring themes that emerged across the workshop regarding best practice, such as: When and how to use QM/MM Structure / model preparation and validation QM/MM modelling/simulation protocol and validation Choice of software and use of high-performance computing Validation, analysis and interpretation of simulation results &nbsp

Interactions between an atomically precise gold nanocluster Au

Nature / Physical science 589, 310 - 314 (2021). doi:10.1038/s41586-020-3000-7, Photosynthetic reaction centres harvest the energy content of sunlight by transporting electrons across an energy-transducing biological membrane. Here we use time-resolved serial femtosecond crystallography1 using an X-ray free-electron laser2 to observe light-induced structural changes in the photosynthetic reaction centre of Blastochloris viridis on a timescale of picoseconds. Structural perturbations first occur at the special pair of chlorophyll molecules of the photosynthetic reaction centre that are photo-oxidized by light. Electron transfer to the menaquinone acceptor on the opposite side of the membrane induces a movement of this cofactor together with lower amplitude protein rearrangements. These observations reveal how proteins use conformational dynamics to stabilize the charge-separation steps of electron-transfer reactions., Published by Macmillan Publishers Limited, part of Springer Nature, London

This report describes work carried out by the BioExcel Centre of Excellence to support and engage with its target user communities during the first 18 months of BioExcel-2, including work done to help ensure that BioExcel activities in all work packages - not only WP3 but also the software and workflow tool development (WP1 & WP2), training (WP4) and sustainability (WP5) - is user driven. During the first half of 2020, as well as executing COVID-19 related research work (see D3.3 - Use Case Progress Report), BioExcel has adapted to support efforts of the wider computational biomolecular research community to tackle the pandemic, including by facilitating research data sharing, support for BioExcel is meeting and exceeding stretch targets on all WP3 KPIs, having supported 600 community members and answered 880 questions on the AskBioExcel support forum and GROMACS mailing list during PM1-PM15, and during PM1-PM18 gathered input from 1200 community members and made available 23 tutorials to users. The Centre has delivered substantial amounts of support, especially to a well-established and ever growing user base corresponding to the core applications GROMACS, PMX and HADDOCK. The execution of free energy calculations by combining functionalities of GROMACS and PMX has been confirmed as an area of very strong interest from both academia and industry. Requests for support are accordingly high, and a pilot project with an industrial partner is in the process of being initiated. The high demand suggests opportunities exist for a BioExcel Legal Entity to sustain itself in part by focusing on meeting this demand. Steps are being taken to support the community in a scalable way by producing tutorials and best practice guides. Workflow tools also play a role, as the containerised execution of large numbers of free energy calculations orchestrated by the PyCOMPSs execution engine to efficiently make use of large-scale parallel HPC resources are enabling rapid massive screening of therapeutics on HPC platforms. As the Use Case work using these tools progresses, the Centre will be able to further leverage the capability demonstrating work done there to support the wider community make use of these tools to perform large-scale free energy calculations. In contrast to GROMACS, PMX and HADDOCK, there is still not a large user base actively using CP2K for biomolecular simulation using the hybrid QM/MM approach. BioExcel is providing live training sessions and creating, improving and updating tutorials that users can study by themselves to get started using CP2K for QM/MM simulation of biomolecular systems, and is in the process of producing a best practice guide. With regards to the GROMACS-CP2K interface, this is now at a maturity level where it can start to be used for Use Case work as planned in the original BioExcel-2 project timeline (see D3.3 - Use Case Progress Report and D1.4 - Project Release of Core Applications). CP2K is simultaneously being optimised for scaling and performance and the interface tested, with work underway to discover and document best practice for joint usage of GROMACS together with CP2K for performing QM/MM simulation including for Use Case demonstrator research work. In the second half of BioExcel-2, the Centre will draw on this experience to support and train the community. In addition to training plans, events are also being planned to help stimulate uptake of CP2K (+GROMACS) for biomolecular research using QM/MM simulation. This is being done by tackling both the hurdle of arriving at a scientifically valid, accuracy-controlled QM treatment of a user���s system using DFT, and issues surrounding usage of CP2K���s particular implementation of a given DFT approach and how to concretely use the software to obtain meaningful results in an efficient manner, with or without GROMACS. S urveys of GROMACS and QM/MM user communities have yielded insights that have already helped shape support activities such as the content of best practice guides, and they will continue to do so. Survey results are also feeding into development work, both by direct identification of feature and performance priorities and, in the case of CP2K, by ensuring that the QM/MM benchmarks used to profile and improve the code���s performance and parallel scaling include a range of system types, sizes, and model parameters that are representative of the priorities of the user community. Further survey work may also help identify additional opportunities for the Centre to facilitate uptake of workflow tools such as the BioExcel building blocks (bioBB) and the PyCOMPSs execution manager, which in a number of BioExcel Use Cases are key to enabling efficient exploitation of large-scale computing resources to demonstrate how to tackle grand scientific challenges., This is the public version of the deliverable where the section "Industry" has been redacted to retain confidentiality.

Proton diffusion (PD) across biological membranes is a fundamental process in many biological systems, and much experimental and theoretical effort has been employed for deciphering it. Here, we report on a spectroscopic probe, which can be tightly tethered to the membrane, for following fast (nanosecond) proton transfer events on the surface of membranes. Our probe is composed of a photoacid that serves as our light-induced proton source for the initiation of the PD process. We use our probe to follow PD, and its pH dependence, on the surface of lipid vesicles composed of a zwitterionic headgroup, a negative headgroup, a headgroup that is composed only from the negative phosphate group, or a positive headgroup without the phosphate group. We reveal that the PD kinetic parameters are highly sensitive to the nature of the lipid headgroup, ranging from a fast lateral diffusion at some membranes to the escape of protons from surface to bulk (and vice versa) at others. By referring to existing theoretical models for membrane PD, we found that while some of our results confirm the quasi-equilibrium model, other results are in line with the nonequilibrium model. peerReviewed

Hydrolysis of nucleoside triphosphate (NTP) plays a key role for the function of many biomolecular systems. However, the chemistry of the catalytic reaction in terms of an atomic-level understanding of the structural, dynamic, and free energy changes associated with it often remains unknown. Here, we report the molecular mechanism of adenosine triphosphate (ATP) hydrolysis in the ATP-binding cassette (ABC) transporter BtuCD-F. Free energy profiles obtained from hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations show that the hydrolysis reaction proceeds in a stepwise manner. First, nucleophilic attack of an activated lytic water molecule at the ATP γ-phosphate yields ADP + HPO42– as intermediate product. A conserved glutamate that is located very close to the γ-phosphate transiently accepts a proton and thus acts as catalytic base. In the second step, the proton is transferred back from the catalytic base to the γ-phosphate, yielding ADP + H2PO4–. These two chemical reaction steps are followed by rearrangements of the hydrogen bond network and the coordination of the Mg2+ ion. The rate constant estimated from the computed free energy barriers is in very good agreement with experiments. The overall free energy change of the reaction is close to zero, suggesting that phosphate bond cleavage itself does not provide a power stroke for conformational changes. Instead, ATP binding is essential for tight dimerization of the nucleotide-binding domains and the transition of the transmembrane domains from inward- to outward-facing, whereas ATP hydrolysis resets the conformational cycle. The mechanism is likely relevant for all ABC transporters and might have implications also for other NTPases, as many residues involved in nucleotide binding and hydrolysis are strictly conserved., ATP hydrolysis in ABC transporter BtuCD follows a three-step mechanism. The reaction free energy in the protein is close to zero and thus cannot provide a power stroke for conformational transitions.

When photoactive molecules interact strongly with confined light modes, new hybrid light–matter states may form: the polaritons. These polaritons are coherent superpositions of excitations of the molecules and of the cavity photon. Recently, polaritons were shown to mediate energy transfer between chromophores at distances beyond the Forster limit. Here we explore the potential of strong coupling for light-harvesting applications by means of atomistic molecular dynamics simulations of mixtures of photoreactive and non-photo-reactive molecules strongly coupled to a single confined light mode. These molecules are spatially separated and present at different concentrations. Our simulations suggest that while the excitation is initially fully delocalized over all molecules and the confined light mode, it very rapidly localizes onto one of the photoreactive molecules, which then undergoes the reaction.

We construct a model describing the response of a hybrid system where the electromagnetic field - in particular, surface plasmon polaritons - couples strongly with electronic excitations of atoms or molecules. Our approach is based on the input-output theory of quantum optics, and in particular it takes into account the thermal and quantum vibrations of the molecules. The latter is described within the $P(E)$ theory analogous to that used in the theory of dynamical Coulomb blockade. As a result, we are able to include the effect of the molecular Stokes shift on the strongly coupled response of the system. Our model then accounts for the asymmetric emission from upper and lower polariton modes. It also allows for an accurate description of the partial decoherence of the light emission from the strongly coupled system. Our results can be readily used to connect the response of the hybrid modes to the emission and fluorescence properties of the individual molecules, and thus are relevant in understanding any utilization of such systems, like coherent light harvesting., 13 pages, 6 figures; included comparison between theory and experiment

Organisms use photo-receptors to react to light. The first step is usually the absorption of a photon by a prosthetic group embedded inside the photo-receptor, often a conjugated chromophore. The electronic changes in the chromophore induced by photo-absorption can trigger a cascade of structural or chemical transformations that culminate into a response to light. Understanding how these proteins have evolved to mediate their activation process has remained challenging because the required time and spacial resolutions are notoriously difficult to achieve experimentally. Therefore, mechanistic insights into photoreceptor activation have been predominantly obtained with computer simulations. Here we briefly outline the challenges associated with such computations and review the progress made in this field.

Nitroxide labels are combined with nucleic acid structures and studied using electron paramagnetic resonance experiments (EPR). As X-ray/NMR structures are unavailable with the nitroxide labels, detailed residue level information, down to atomic resolution, about the effect of these nitroxide labels on local RNA structures is currently lacking. This information is critical to evaluate the choice of spin label. In this study, we compare and contrast the effect of TEMPO-based (NT) and rigid spin (Ç) labels (in both 2’-O methylated and not-methylated forms) on RNA duplexes. We also investigate sequence-dependent effects of NT label on RNA duplex along with the more complex G-quadruplex RNA. Distances measured from molecular dynamics simulations between the two spin labels are in agreement with the EPR experimental data. To understand the effect of labeled oligonucleotides on the structure, we studied the local base pair geometries and global structure in comparison with the unlabeled structures. Based on the structural analysis, we can conclude that TEMPO-based and Ç labels do not significantly perturb the base pair arrangements of the native oligonucleotide. When experimental structures for the spin labelled DNA/RNA molecules are not available, general framework offered by the current study can be used to provide information critical to the choice of spin labels to facilitate future EPR studies.Graphical abstract

When the enhanced electromagnetic field of a confined light mode interacts with photoactive molecules, the system can be driven into the regime of strong coupling, where new hybrid light-matter states, polaritons, are formed. Polaritons, manifested by the Rabi split in the dispersion, have shown potential for controlling the chemistry of the coupled molecules. Here, we show by angle-resolved steady-state experiments accompanied by multi-scale molecular dynamics simulations that the molecular Stokes shift plays a significant role in the relaxation of polaritons formed by organic molecules embedded in a polymer matrix within metallic Fabry-Pérot cavities. Our results suggest that in the case of Rhodamine 6G, a dye with a significant Stokes shift, excitation of the upper polariton leads to a rapid localization of the energy into the fluorescing state of one of the molecules, from where the energy scatters into the lower polariton (radiative pumping), which then emits. In contrast, for excitonic J-aggregates with a negligible Stokes shift, the fluorescing state does not provide an efficient relaxation gateway. Instead, the relaxation is mediated by exchanging energy quanta matching the energy gap between the dark states and lower polariton into vibrational modes (vibrationally assisted scattering). To understand better how the fluorescing state of a molecule that is not strongly coupled to the cavity can transfer its excitation energy to the lower polariton in the radiative pumping mechanism, we performed multi-scale molecular dynamics simulations. The results of these simulations suggest that non-adiabatic couplings between uncoupled molecules and the polaritons are the driving force for this energy transfer process.

It is included two versions of this item: the Accepted Version which is already Open Access and the Published Version which is under an embargo period till 2022-03-09., Coupling molecules to the confined light modes of an optical cavity is showing great promise for manipulating chemical reactions. However, to fully exploit this principle and use cavities as a new tool for controlling chemistry, a complete understanding of the effects of strong light-matter coupling on molecular dynamics and reactivity is required. While quantum chemistry can provide atomistic insight into the reactivity of uncoupled molecules, the possibilities to also explore strongly coupled systems are still rather limited due to the challenges associated with an accurate description of the cavity in such calculations. Despite recent progress in introducing strong coupling effects into quantum chemistry calculations, applications are mostly restricted to single or simplified molecules in ideal lossless cavities that support a single light mode only. However, even if commonly used planar mirror micro-cavities are characterized by a fundamental mode with a frequency determined by the distance between the mirrors, the cavity energy also depends on the wave vector of the incident light rays. To account for this dependency, called cavity dispersion, in atomistic simulations of molecules in optical cavities, we have extended our multi-scale molecular dynamics model for strongly coupled molecular ensembles to include multiple confined light modes. To validate the new model, we have performed simulations of up to 512 Rhodamine molecules in red-detuned Fabry-Pérot cavities. The results of our simulations suggest that after resonant excitation into the upper polariton at a fixed wave vector, or incidence angle, the coupled cavity-molecule system rapidly decays into dark states that lack dispersion. Slower relaxation from the dark state manifold into both the upper and lower bright polaritons causes observable photo-luminescence from the molecule-cavity system along the two polariton dispersion branches that ultimately evolves toward the bottom of the lower polariton branch, in line with experimental observations. We anticipate that the more realistic cavity description in our approach will help to better understand and predict how cavities can modify molecular properties, This work was supported by the Academy of Finland (Grant No. 323996 to G.G.) as well as the European Research Council (Grant No. ERC-2016-StG-714870 to J.F.) and the Spanish Ministry for Science, Innovation, and Universities—AEI (Grant No. RTI2018-099737-B-I00 to J.F.). We thank the Center for Scientific Computing (CSC-IT Center for Science) for generous computational resources

Ligand-stabilized, atomically precise gold nanoclusters with a metal core of a uniform size of just 1–3 nm constitute an interesting class of nanomaterials with versatile possibilities for applications due to their size-dependent properties and modifiable ligand layers. The key to extending the usability of the clusters in applications is to understand the chemical bonding in the ligand layer as a function of cluster size and ligand structure. Previously, it has been shown that monodispersed gold nanoclusters, stabilized by meta-mercaptobenzoic acid (m-MBA or 3-MBA) ligands and with sizes of 68–144 gold atoms, show ambient stability. Here we show that a combination of nuclear magnetic resonance spectroscopy, UV–vis absorption, infrared spectroscopy, molecular dynamics simulations, and density functional theory calculations reveals a distinct chemistry in the ligand layer, absent in other known thiol-stabilized gold nanoclusters. Our results imply a low-symmetry C1 ligand layer of 3-MBA around the gold cor...

We have investigated the dynamics of strongly coupled modes of surface plasmon polaritons (SPPs) and fluorescent molecules by analyzing their scattered emission polarization. While the scattered emission of SPPs is purely transverse magnetic (TM) polarized, the strong coupling with molecules induces transverse electric (TE) polarized emission via the partial molecular nature of the formed SPP–molecule polariton mode. We observe that the TM/TE ratio of the polariton emission follows the contribution of the molecular excited states in this hybrid mode. By using several types of molecules, we observe that, in addition to the coupling strength, which determines the contribution of the molecular excited states, also the Stokes shift of the molecule fluorescence influences the polarization of the emission: the larger the shift, the lower the TE-polarized emission. We argue that due to random orientation of the molecules, the emission of a fully coherent SPP–molecule polariton should be purely TM-polarized, like...

Correct protonation of titratable groups in biomolecules is crucial for their accurate description by molecular dynamics simulations. In the context of constant pH simulations, an additional protonation degree of freedom is introduced for each titratable site, allowing the protonation state to change dynamically with changing structure or electrostatics. Here, we extend previous approaches for an accurate description of chemically coupled titrating sites. A second reaction coordinate is used to switch between two tautomeric states of an amino acid with chemically coupled titratable sites, such as aspartate (Asp), glutamate (Glu), and histidine (His). To this aim, we test a scheme involving three protonation states. To facilitate charge neutrality as required for periodic boundary conditions and Particle Mesh Ewald (PME) electrostatics, titration of each respective amino acid is coupled to a “water” molecule that is charged in the opposite direction. Additionally, a force field modification for Amber99sb is introduced and tested for the description of carboxyl group protonation. Our three states model is tested by titration simulations of Asp, Glu, and His, yielding a good agreement, reproducing the correct geometry of the groups in their different protonation forms. We further show that the ion concentration change due to the neutralizing “water” molecules does not significantly affect the protonation free energies of the titratable groups, suggesting that the three states model provides a good description of biomolecular dynamics at constant pH.

Journal of the American Chemical Society 138(51), 16620 - 16631 (2016). doi:10.1021/jacs.6b05609, There has been considerable debate on the existence of a low-barrier hydrogen bond (LBHB) in the photoactive yellow protein (PYP). The debate was initially triggered by the neutron diffraction study of Yamaguchi et al. ( Proc. Natl. Acad. Sci., U. S. A., 2009, 106, 440−444) who suggested a model in which a neutral Arg52 residue triggers the formation of the LBHB in PYP. Here, we present an alternative model that is consistent within the error margins of the Yamaguchi structure factors. The model explains an increased hydrogen bond length without nuclear quantum effects and for a protonated Arg52. We tested both models by calculations under crystal, solution, and vacuum conditions. Contrary to the common assumption in the field, we found that a single PYP in vacuum does not provide an accurate description of the crystal conditions but instead introduces strong artifacts, which favor a LBHB and a large 1H NMR chemical shift. Our model of the crystal environment was found to stabilize the two Arg52 hydrogen bonds and crystal water positions for the protonated Arg52 residue in free MD simulations and predicted an Arg52 pKa upshift with respect to PYP in solution. The crystal and solution environments resulted in almost identical 1H chemical shifts that agree with NMR solution data. We also calculated the effect of the Arg52 protonation state on the LBHB in 3D nuclear equilibrium density calculations. Only the charged crystal structure in vacuum supports a LBHB if Arg52 is neutral in PYP at the previously reported level of theory ( J. Am. Chem. Soc., 2014, 136, 3542−3552). We attribute the anomalies in the interpretation of the neutron data to a shift of the potential minimum, which does not involve nuclear quantum effects and is transferable beyond the Yamaguchi structure., Published by American Chemical Society, Washington, DC

In constant pH molecular dynamics simulations, the protonation states of titratable sites can respond to changes of the pH and of their electrostatic environment. Consequently, the number of protons bound to the biomolecule, and therefore the overall charge of the system, fluctuates during the simulation. To avoid artifacts associated with a non-neutral simulation system, we introduce an approach to maintain neutrality of the simulation box in constant pH molecular dynamics simulations, while maintaining an accurate description of all protonation fluctuations. Specifically, we introduce a proton buffer that, like a buffer in experiment, can exchange protons with the biomolecule enabling its charge to fluctuate. To keep the total charge of the system constant, the uptake and release of protons by the buffer are coupled to the titration of the biomolecule with a constraint. We find that, because the fluctuation of the total charge (number of protons) of a typical biomolecule is much smaller than the number of titratable sites of the biomolecule, the number of buffer sites required to maintain overall charge neutrality without compromising the charge fluctuations of the biomolecule, is typically much smaller than the number of titratable sites, implying markedly enhanced simulation and sampling efficiency.

The pKa of the p-mercaptobenzoic acid (pMBA) ligands in the Au102(pMBA)44 nanocluster was measured by using acid–base and IR titration. The observed macroscopic pKa = 6.18 ± 0.05 is significantly more basic than that of free pMBA (pKa = 4.16), and the protonation behavior is anticooperative according to the Hill coefficient n = 0.64 ± 0.04. The cluster is truly water-soluble when more than 22 and insoluble when fewer than 7 ligands are in the deprotonated state. In order to obtain more insight into the anticooperative character, the cluster was modeled at pH ∼6.2 using constant pH molecular dynamics simulations. The pKa values of the individual pMBAs are in the range of 5.18–7.58, depending on the positions of the ligands, generating a nonuniform charge distribution on the cluster surface. The cluster interactions with inorganic and biological environment depend on the surface charge distribution, stressing the importance of understanding the protonation state of the cluster.

Our work based on previous studies [1, 2] confirms, that simple aluminum nanostructures can be utilized as effective plasmonic resonators over a broad range of frequencies and wavelengths. The nanostructured surfaces, fabricated by electron-beam lithography demonstrated relatively narrow-band resonances and are suitable for various plasmonic applications ranging from metal enhanced fluorescence to strong-coupling [1, 2, 3, 4, 5] experiments. We represent data for molecule-plasmon coupling near the strong coupling limit and demonstrate that these aluminum structures do act as fluorescence increasing substrates. In this work, we used two different types of dyes. We studied the narrow band j-aggregate forming TDBC with almost no Stokes-shift and a recently developed large Stokes-shift dye commercially available under the name ATTO 490LS. Anti-crossing behavior was observed for both dyes, but a clear Rabi split for the ATTO 490LS was not fully reached. We observed a Rabi split of more than 160 meV for the TDBC sample (Fig. 1) and enhanced selectively the fluorescence of the ATTO 490LS dye more than 3.5 times.

The fluorescent protein Dronpa undergoes reversible photoswitching reactions between the bright ‘on’ and dark ‘off’ states via photoisomerisation and proton transfer reactions. We report the room temperature crystal structure of the fast switching Met159Thr mutant of Dronpa at 2.0 A resolution in the bright on state. Structural differences with the wild type include shifted backbone positions of strand β8 containing Thr159 as well as an altered A-C dimer interface involving strands β7, β8, β10, and β11. The Met159Thr mutation increases the cavity volume for the p-hydroxybenzylidene-imidazolinone chromophore as a result of both the side chain difference and the backbone positional differences.