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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

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

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

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...

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.

The vibronic spectra of the green fluorescent protein chromophore analogues p-hydroxybenzylidene-2,3-dimethylimidazolinone (HBDI) and 3,5-tert-butyl-HBDI (35Bu) are similar in the vacuum, but very different in water or ethanol. To understand this difference, we have computed the vibrationally resolved solution spectra of these chromophores, using the polarizable continuum model (PCM) to account for solvent effects on the (harmonic) potential energy surfaces (PES). In agreement with experiment, we found that the vibrational progression increases with the polarity of the solvent, but we could neither reproduce the broadening, nor the large difference between the absorption spectra of HBDI and 35Bu. To account for the inhomogeneous broadening of the solution spectra, we used two approaches. In the first, we estimated the polar broadening from the solvent reorganization energy upon photo-excitation, using the state-specific PCM implementation. In the second, we estimated the broadening from the variance of the vertical excitation energies in molecular dynamics trajectories. Although we found good agreement for the lineshape of 35Bu in ethanol, and to a lesser extent in water, we highly underestimated the broadening for HBDI. To resolve this discrepancy, we explored the PES of HBDI in water and found that in contrast to the PCM result, the ground-state geometry is not planar in explicit solvent. We furthermore found that nonplanar geometries enhance the intramolecular charge transfer upon excitation. Therefore, the solvent reorganization and broadening are much larger and we speculate that the much broader spectrum of HBDI in water is due to the population of nonplanar geometries.

We describe a method to measure ultrafast protein structural changes using time-resolved wide-angle X-ray scattering at an X-ray free-electron laser. We demonstrated this approach using multiphoton excitation of the Blastochloris viridis photosynthetic reaction center, observing an ultrafast global conformational change that arises within picoseconds and precedes the propagation of heat through the protein. This provides direct structural evidence for a 'protein quake': the hypothesis that proteins rapidly dissipate energy through quake-like structural motions. peerReviewed

Hydration shells around ions are crucial for many fundamental biological and chemical processes. Their local physicochemical properties are quite different from those of bulk water and hard to probe experimentally. We address this problem by combining soft X-ray spectroscopy using a liquid jet and molecular dynamics (MD) simulations together with ab initio electronic structure calculations to elucidate the water–ion interaction in a MgCl2 solution at the molecular level. Our results reveal that salt ions mainly affect the electronic properties of water molecules in close vicinity and that the oxygen K-edge X-ray emission spectrum of water molecules in the first solvation shell differs significantly from that of bulk water. Ion-specific effects are identified by fingerprint features in the water X-ray emission spectra. While Mg2+ ions cause a bathochromic shift of the water lone pair orbital, the 3p orbital of the Cl– ions causes an additional peak in the water emission spectrum at around 528 eV. peerReviewed

We performed ab initio excited-state molecular dynamics simulations of a gas-phase photoexcited protonated Schiff base (C1-N2═C3-C4═C5-C6) to search for control mechanisms of its photoisomerization. The excited molecule twists by ∼90° around either the N2C3 bond or the C4C5 bond and relaxes to the ground electronic state through a conical intersection with either a trans or cis outcome. We show that a large initial distortion of several dihedral angles and a specific normal vibrational mode combining pyramidalization and double-bond twisting can lead to a preferential rotation of atoms around the C4C5 bond. We also show that selective pretwisting of several dihedral angles in the initial ground state thermal ensemble (by analogy to a protein pocket) can significantly increase the fraction of photoreactive (cis → trans) trajectories. We demonstrate that new ensembles with higher degrees of control over the photoisomerization reaction can be obtained by a computational directed evolution approach on the ensembles of molecules with the pretwisted geometries.

Many biological processes depend on detecting and responding to light. The response is often mediated by a structural change in a protein that begins when absorption of a photon causes isomerization of a chromophore bound to the protein. Pande et al. used x-ray pulses emitted by a free electron laser source to conduct time-resolved serial femtosecond crystallography in the time range of 100 fs to 3 ms. This allowed for the real-time tracking of the trans-cis isomerization of the chromophore in photoactive yellow protein and the associated structural changes in the protein.Science, this issue p. 725A variety of organisms have evolved mechanisms to detect and respond to light, in which the response is mediated by protein structural changes after photon absorption. The initial step is often the photoisomerization of a conjugated chromophore. Isomerization occurs on ultrafast time scales and is substantially influenced by the chromophore environment. Here we identify structural changes associated with the earliest steps in the trans-to-cis isomerization of the chromophore in photoactive yellow protein. Femtosecond hard x-ray pulses emitted by the Linac Coherent Light Source were used to conduct time-resolved serial femtosecond crystallography on photoactive yellow protein microcrystals over a time range from 100 femtoseconds to 3 picoseconds to determine the structural dynamics of the photoisomerization reaction.

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.

Atomistic QM/MM simulations have been carried out on the complete photocycle of Photoactive Yellow Protein, a bacterial photoreceptor, in which blue light triggers isomerization of a covalently bound chromophore. The "chemical role" of the protein cavity in the control of the photoisomerization step has been elucidated. Isomerization is facilitated due to preferential electrostatic stabilization of the chromophore's excited state by the guanidium group of Arg52, located just above the negatively charged chromophore ring. In vacuo isomerization does not occur. Isomerization of the double bond is enhanced relative to isomerization of a single bond due to the steric interactions between the phenyl ring of the chromophore and the side chains of Arg52 and Phe62. In the isomerized configuration (ground-state cis), a proton transfer from Glu46 to the chromophore is far more probable than in the initial configuration (ground-state trans). It is this proton transfer that initiates the conformational changes within the protein, which are believed to lead to signaling.

The cellular energy machinery depends on the presence and properties of protons at or in the vicinity of lipid membranes. To asses the energetics and mobility of a proton near a membrane, we simulated an excess proton near a solvated DMPC bilayer at 323 K, using a recently developed method to include the Grotthuss proton shuttling mechanism in classical molecular dynamics simulations. We obtained a proton surface affinity of −13.0 ± 0.5 kJ mol−1. The proton interacted strongly with both lipid headgroup and linker carbonyl oxygens. Furthermore, the surface diffusion of the proton was anomalous, with a subdiffusive regime over the first few nanoseconds, followed by a superdiffusive regime. The time- and distance dependence of the proton surface diffusion coefficient within these regimes may also resolve discrepancies between previously reported diffusion coefficients. Our simulations show that the proton anomalous surface diffusion originates from restricted diffusion in two different surface-bound states, interrupted by the occasional bulk-mediated long-range surface diffusion. Although only a DMPC membrane was considered in this work, we speculate that the restrictive character of the on-surface diffusion is highly sensitive to the specific membrane conditions, which can alter the relative contributions of the surface and bulk pathways to the overall diffusion process. Finally, we discuss the implications of our findings for the energy machinery.

We present Hydrogen Dynamics (HYDYN), a method that allows explicit proton transfer in classical force field molecular dynamics simulations at thermodynamic equilibrium. HYDYN reproduces the characteristic properties of the excess proton in water, from the special pair dance, to the continuous fluctuation between the limiting Eigen and Zundel complexes, and the water reorientation beyond the first solvation layer. Advantages of HYDYN with respect to existing methods are computational efficiency, microscopic reversibility, and easy parameterization for any force field peerReviewed

The first excited state of the Photoactive Yellow Protein chromophore exhibits a strong charge transfer character and the dipole moments of the excited and ground states differ significantly. Furthermore, the excited state charge distribution changes during the isomerization of this chromophore. These observations suggest that external electric fields can be used to control photo-isomerization, providing a new concept for developing photochromic devices, such as e-paper or optical memory. To test this idea, we performed excited state dynamics simulations and static calculations of a PYP chromophore analogue (pCK − ) in an external electric field. By adjusting direction and strength of the field, we were able to control both selectivity ( i.e., which bond isomerizes) and efficiency (excited state lifetime) of the isomerization process. Simulations like these could potentially be useful in validating whether a given chromophore could be suitable for electrochromic applications.

[Introduction] The concentration of hydronium and hydroxide at the water-air interface has been under debate for a long time. Recent evidence from a range of experiments and theoretical calculations strongly suggests the water surface is somewhat acidic. Using novel polarizable models we have performed potential of mean force calculations of a hydronium ion, a hydroxide ion and a water molecule in a water droplet and a water slab and we were able to rationalize that hydronium, but not hydroxide, is slightly enriched at the surface for two reasons. First, because the hydrogen-bond acceptance capacity of hydronium is weaker than water it is more favorable to have the hydronium oxygen on the surface. Second, hydroxide ions are expelled from the surface of droplets, due to the entropy being lower when a hydroxide ion is hydrated on the surface. As a result, the water dissociation constant pK w increases slightly near the surface. The results are corroborated by calculations of surface tension of NaOH solutions that are in reasonable agreement with experiment. The structural and thermodynamic interpretation of hydronium and hydroxide hydration provided by these calculations opens the route to a better understanding of atmospheric- and surface chemistry. peerReviewed

The complete active space self-consistent field (CASSCF) method is one of the most used approaches to explore theoretically non-adiabatic photochemical processes in medium-size molecular systems. It is also frequently utilized in direct dynamics studies because this method offers a reliable description of the electronic state mixing in the regions of surface crossings (conical intersections). In this context, however, the large computational demand required to perform such on-the-fly molecular dynamics simulations using CASSCF as the electronic structure method means that only relatively small active space can be handled (typically not more than 10 electrons distributed in 10 orbitals). In this article, we present some guidelines to reduce the active space size in CASSCF calculations in order to decrease the computational cost necessary to perform, for example, molecular dynamics simulations. Three important criteria are considered: (i) the degradation of the accuracy in the description of the potential energy surface following the reduction of the active space, (ii) the stability of the reduced active space across the global potential energy surface, and (iii) the cost of the CASSCF calculation using the reduced active space. Two illustrations are given. The first one is the benzene to benzvalene S 1 photochemical pathway, the second one is the photoisomerization of thiomethyl para -coumaric acid, the chromophore in photoactive yellow protein.

Long chain fatty acids are biologically important molecules with complex and pH sensitive aggregation behavior. The carboxylic head group of oleic acid is ionizable, with the pKa shifting to larger values, even above a value of 7, in certain aggregate states. While experiments have determined the macroscopic phase behavior, we have yet to understand the molecular level details for this complex behavior. This level of detail is likely required to fully appreciate the role of fatty acids in biology and for nanoscale biotechnological and industrial applications. Here, we introduce the use of constant pH molecular dynamics (MD) simulations with the coarse-grained MARTINI model and apply the method to oleic acid aggregates and a model lipid bilayer. By running simulations at different constant pH values, we determined titration curves and the resulting pKa for oleic acid in different environments. The coarse-grained model predicts positive pKa shifts, with a shift from 4.8 in water to 6.5 in a small micelle, and 6.6 in a dioleoylphosphatidylcholine (DOPC) bilayer, similar to experimental estimates. The size of the micelles increased as the pH increased, and correlated with the fraction of deprotonated oleic acid. We show this combination of constant pH MD and the coarse-grained MARTINI model can be used to model pH-dependent surfactant phase behavior. This suggests a large number of potential new applications of large-scale MARTINI simulations in other biological systems with ionizable molecules.

Because of the high intensity, X-ray free electron lasers allow one to create and probe double core ionized states in molecules. The decay of these multiple core ionized states crucially determines the evolution of radiation damage in single molecule diffractive imaging experiments. Here we have studied the Auger decay in hydrides of first row elements after single and double core ionization by quantum mechanical ab initio calculations. In our approach the continuum wave function of the emitted Auger electron is expanded into spherical harmonics on a radial grid. The obtained decay rates of double K-shell vacancies were found to be systematically larger than those for the respective single K-shell vacancies, markedly exceeding the expected factor of two. This enhancement is attributed to the screening effects induced by the core hole. We propose a simple model, which is able to predict core hole decay rates in molecules with low Z elements based on the electron density in the vicinity of the core hole. peerReviewed

We have performed ab initio excited-state molecular dynamics simulations of an isolated photo-excited protonated Schiff base (C1-N2=C3-C4=C5-C6) to search for mechanisms that control its photoisomerization outcome, such as the bond selectivity and (trans, cis) conformation. We observe that the photo-excited molecule twists around the N2C3 bond (∼80% cases of the thermal ensemble) or the C4C5 bond, and relaxes back to the ground electronic state with either a trans or cis outcome. First, we show that a significant initial distortion of several selected dihedral angles can preferentially guide the excited-state dynamics towards twisting of the C4C5 bond. Next, we examine if the bond selectivity can be controlled by the vibrational pre-excitation of the molecule along individual normal modes. We find that pre-excitation of only one of the modes, which contains a prominent propelling motion of the C4C5 bond with respect to the neighboring C3C4 single bond, leads to twisting of the C4C5 bond. Normal mode decomposition of the ground state thermal ensemble shows that in starting structures in which this same mode is pre-excited by 1-2 kBT thermal energy, the twisting of C4C5 occurs with a 30-50% probability. Finally, we find that the (trans, cis) outcome of the reaction can be controlled by selective pre-twisting of several dihedral angles, while keeping other degrees of freedom thermally excited. This choice was justified by the observed pre-twisting of retinal chromophore in rhodopsin, which exhibits 65% cis to trans transition. In the thermal ensemble with such pre-twisted dihedrals, we observe on the excited state potential energy surface synchronized twisting of CN2C3C and HN2C3H torsional angles surrounding the isomerizing N2C3 bond, which significantly increases the fraction of reactive (cis to trans) trajectories. These observations provide crucial understanding of natural photoisomerization mechanisms and their potential use in synthetic molecules.

Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have become a popular tool for investigating chemical reactions in condensed phases. In QM/MM methods, the region of the system in which the chemical process takes place is treated at an appropriate level of quantum chemistry theory, while the remainder is described by a molecular mechanics force field. Within this approach, chemical reactivity can be studied in large systems, such as enzymes. In the first part of this contribution, the basic methodology is briefly reviewed. The two most common approaches for partitioning the two subsystems are presented, followed by a discussion on the different ways of treating interactions between the subsystems. Special attention is given on how to deal with situations in which the boundary between the QM and MM subsystems runs through one or more chemical bonds. The second part of this contribution discusses what properties of larger system can be obtained within the QM/MM framework and how. Finally, as an example of a QM/MM application in practice, the third part presents an overview of recent QM/MM molecular dynamics simulations on photobiological systems. In addition to providing quantities that are experimentally accessible, such as structural intermediates, fluorescence lifetimes, quantum yields and spectra, the QM/MM simulations also provide information that is much more difficult to measure experimentally, such as reaction mechanisms and the influence of individual amino acid residues. Key word: Quantum mechanics, Molecular mechanics, QM/MM, Molecular dynamics

Nucleic acid force fields have been shown to reproduce structural properties of DNA and RNA very well, but comparative studies with respect to thermodynamic properties are rare. As a test for thermodynamic properties, we have computed hydration free energies and chloroform-to-water partition coefficients of nucleobases using the AMBER-99, AMBER-gaff, CHARMM-27, GROMOS-45a4/53a6 and OPLS-AA force fields. A mutual force field comparison showed a very large spread in the calculated thermodynamic properties, demonstrating that some of the parameter sets require further optimization. The choice of solvent model used in the simulation does not have a significant effect on the results. Comparing the hydration free energies obtained by the various force fields to the adenine and thymine experimental values showed a very large deviation for the GROMOS and AMBER parameter sets. Validation against experimental partition coefficients showed good agreement for the CHARMM-27 parameter set. In view of mutation studies, differences in partition coefficient between two bases were also compared, and good agreement between experiments and calculations was found for the AMBER-99 parameter set. Overall, the CHARMM-27 parameter set performs best with respect to the thermodynamic properties tested here. © 2012 Wiley Periodicals, Inc.

The high intensity of free electron lasers opens up the possibility to perform single-shot molecule scattering experiments. However, even for small molecules, radiation damage induced by absorp- tion of high intense x-ray radiation is not yet fully understood. One of the striking effects which occurs under intense x-ray illumination is the creation of double core ionized molecules in con- siderable quantity. To provide insight into this process, we have studied the dynamics of water molecules in single and double core ionized states by means of electronic transition rate calcula- tions and ab initio molecular dynamics (MD) simulations. From the MD trajectories, photoioniza- tion and Auger transition rates were computed based on electronic continuum wavefunctions ob- tained by explicit integration of the coupled radial Schrödinger equations. These rates served to solve the master equations for the populations of the relevant electronic states. To account for the nuclear dynamics during the core hole lifetime, the calculated electron emission spectra for differ- ent molecular geometries were incoherently accumulated according to the obtained time-dependent populations, thus neglecting possible interference effects between different decay pathways. We find that, in contrast to the single core ionized water molecule, the nuclear dynamics for the double core ionized water molecule during the core hole lifetime leaves a clear fingerprint in the result- ing electron emission spectra. The lifetime of the double core ionized water was found to be sig- nificantly shorter than half of the single core hole lifetime.

Carbonic anhydrases (CAs) are enzymes whose endogenous reaction is the reversible hydration of CO(2) to give HCO(3)(-) and a proton. CA are also known to exhibit weak and promiscuous esterase activity toward activated esters. Here, we report a series of findings obtained with a set of CA inhibitors that showed quite unexpectedly that the compounds were both inhibitors of CO(2) hydration and substrates for the esterase activity of CA. The compounds comprised a monosaccharide core with the C-6 primary hydroxyl group derivatized as a sulfamate (for CA recognition). The remaining four sugar hydroxyl groups were acylated. Using protein X-ray crystallography, the crystal structures of human CA II in complex with four of the sulfamate inhibitors were obtained. As expected, the four structures displayed the canonical CA protein-sulfamate interactions. Unexpectedly, a free hydroxyl group was observed at the anomeric center (C-1) rather than the parent C-1 acyl group. In addition, this hydroxyl group is observed axial to the carbohydrate ring while in the parent structure it is equatorial. A mechanism is proposed that accounts for this inversion of stereochemistry. For three of the inhibitors, the acyl groups at C-2 or at C-2 and C-3 were also absent with hydroxyl groups observed in their place and retention of stereochemistry. With the use of electrospray ionization-Fourier transform ion cyclotron resonance-mass spectrometry (ESI-FTICR-MS), we observed directly the sequential loss of all four acyl groups from one of the carbohydrate-based sulfamates. For this compound, the inhibitor and substrate binding mode were further analyzed using free energy calculations. These calculations suggested that the parent compound binds almost exclusively as a substrate. To conclude, we have demonstrated that acylated carbohydrate-based sulfamates are simultaneously inhibitor and substrate of human CA II. Our results suggest that, initially, the substrate binding mode dominates, but following hydrolysis, the ligand can also bind as a pure inhibitor thereby competing with the substrate binding mode.

International audience; We have performed ab initio CASSCF, CASPT2, and EOM-CCSD calculations on doubly deprotonated p-coumaric acid (pCA2−), the chromophore precursor of the photoactive yellow protein. The results of the calculations demonstrate that pCA2− can undergo only photoisomerization of the double bond. In contrast, the chromophore derivative with the acid replaced by a ketone (p-hydroxybenzylidene acetone, pCK−) undergoes both single- and double-bond photoisomerization, with the single-bond relaxation channel more favorable than the double-bond channel. The substitution alters the nature of the first excited states and the associated potential energy landscape. The calculations show that the electronic nature of the first two (π,π*) excited states are interchanged in vacuo due to the substitution. In pCK−, the first excited state is a charge-transfer (CT π,π*) state, in which the negative charge has migrated from the phenolate ring onto the alkene tail of the chromophore, whereas the locally excited (LE π,π*) state, in which the excitation involves the orbitals on the phenol ring, lies higher in energy and is the fourth excited state. In pCA2−, the CT state is higher in energy due the presence of a negative charge on the tail of the chromophore, and the first excited state is the LE state. In isolated pCA2−, there is a 68 kJ/mol barrier for double-bond photoisomerization on the potential energy surface of this LE state. In water, however, hydrogen bonding with water molecules reduces this barrier to 9 kJ/mol. The barrier separates the local trans minimum near the Franck−Condon region from the global minimum on the excited-state potential energy surface. The lowest energy conical intersection was located near this minimum. In contrast to pCK−, single-bond isomerization is highly unfavorable both in the LE and CT states of pCA2−. These results demonstrate that pCA2− can only decay efficiently in water and exclusively by double-bond photoisomerization. These findings provide a rationale for the experimental observations that pCA2− has both a longer excited-state lifetime and a higher isomerization quantum yield than pCK−.

International audience; We have performed excited-state dynamics simulations of a Photoactive Yellow Protein chromophore analogue in water. The results of the simulations demonstrate that in water the chromophore predominantly undergoes single-bond photoisomerization, rather than double-bond photoisomerization. Despite opposite charge distributions in the chromophore, excited-state decay takes place very efficiently from both single- and double-bond twisted minima in water. Radiationless decay is facilitated by ultrafast solvent reorganization, which stabilizes both minima by specific hydrogen bond interactions. Changing the solvent to the slightly more viscous D(2)O leads to an increase of the excited-state lifetime. Together with previous simulations, the present results provide a complete picture of the effect of the protein on the photoisomerization of the chromophore in PYP: the positive guanidinium group of Arg52 favors double-bond isomerization over single-bond isomerization by lowering the barrier for double-bond isomerization, while the hydrogen bonds with Tyr42 and Glu46 enhance deactivation from the double-bond twisted minimum.

Organisms have evolved a wide variety of mechanisms to utilize and respond to light. In many cases, the biological response is mediated by structural changes that follow photon absorption. These reactions typically occur at femto- to picosecond timescales. As the relevant time and spatial resolutions are notoriously hard to access experimentally, molecular dynamics (MD) simulations are the method of choice to study such ultrafast processes. In the simulations, a multiconfigurational quantum mechanical (QM) description (CASSCF, CASPT2) is required to model the electronic rearrangement of those parts of the system that are involved in the absorption. For the remainder, typically consisting of the apoprotein and the solvent, a simple forcefield model (MM) suffices. QM/MM gradients have to be computed on-the-fly, and surface hopping procedures are needed to model the excited state decay. In this chapter, the computational framework underlying the atomistic simulation of photochemical events is reviewed and a few representative applications are discussed that demonstrate the validity of hybrid QM/MM approaches for photobiological reactions. Keywords: excited state dynamics; force field; molecular mechanics; molecular dynamics; molecular dynamics

We have performed excited-state dynamics simulations of the Arg52Gln (R52Q) mutant of photoactive yellow protein (PYP). The results of these simulations demonstrate that in the mutant the primary events after photoexcitation are different from those in the wild-type. In the mutant, the chromophore predominantly undergoes single bond photoisomerization, whereas in the wild-type, photoisomerization of the double bond occurs. Furthermore, the excited-state lifetime is around three times longer than in wild-type PYP, which agrees well with recent transient absorption measurements. In 20% of the trajectories, we observe the formation of a photoproduct that has the carbonyl oxygen atom of the chromophore flipped by almost 180°, disrupting the hydrogen bond between the chromophore and the backbone amino group of Cys69. This observation, in combination with the fact that the mutant is photoactive, suggests that the break of the hydrogen bond is the key step in the photoactivation process rather than the double bo...

Three approximate switching algorithms for trajectory surface hopping calculations are presented using simple models to describe the dependence of the hopping probability on the nonadiabatic coupling strength. The switching algorithms are applied to the calculation of the electronic deexcitation in ethylene, methaniminium ion and trans-azobenzene. Compared with the results from the standard fewest switching algorithm (FSA), the simplest approximation based on a local diabatic representation shows some qualitative failures and overestimates the decay times severely. The other two approximate switching algorithms incorporate stochastic features and reproduce the FSA results well, with a deviation of typically 20–30% in the computed decay times. They offer a simple and efficient description of the nonadiabatic dynamics of the investigated systems.

Molecular dynamics simulation techniques, together with semiempirical PM3 calculations, have been used to investigate the effect of photoisomerization of the 4-hydroxy-cinnamic acid chromophore on the structural properties of the photoactive yellow protein (PYP) from Ectothiorodospira halophila. In this bacteria, exposure to blue light leads to a negative photoactic response. The calculations suggest that the isomerization does not directly destabilize the protein. However, because of the isomerization, a proton transfer from a glutamic acid residue (Glu46) to the phenolate oxygen atom of the chromophore becomes energetically favorable. The proton transfer initiates conformational changes within the protein, which are in turn believed to lead to signaling. Proteins 2002;48:212–219. © 2002 Wiley-Liss, Inc.

Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation. The data reveal a twist of the D-ring, which leads to partial detachment of the chromophore from the protein. Unexpectedly, the conserved so-called pyrrole water is photodissociated from the chromophore, concomitant with movement of the A-ring and a key signaling aspartate. The changes are wired together by ultrafast backbone and water movements around the chromophore, channeling them into signal transduction towards the output domains. We suggest that the observed collective changes are important for the phytochrome photoresponse, explaining the earliest steps of how plants, fungi and bacteria sense red light.

Modified and unmodified yeast tRNA(Phe) in solution was simulated to understand the effect of nucleotide modifications on the dynamics of tRNA. High performance computing techniques were employed to obtain a “dynamic picture” at spacial and time resolutions hardly accessible experimentally for these systems. Local flexibility, secondary and tertiary structure, global rearrangements and movements of the whole tRNA were probed by a microsecond of all atom explicit solvent molecular dynamics simulations.The results of our simulations give new insight on experimentally observed biological impact of nucleotide modifications. Amongst other results we find that tRNA modification leads to a decrease in secondary structure and tertiary interactions in the anticodon stem loop. Nucleotides U16 and U17 show different orientations when modified to dihydrouridine. Modification of A58 to 1-methyladenosine causes local rearrangements in the elbow region. Implications of our results on external factor binding are discussed.

The ultra intense femtosecond X-ray pulses from free electron lasers that are being developed in Hamburg and Stanford hold the promise to obtain X-ray scattering information from single molecules, even from proteins [1]. This technique could enable monitoring ultrafast atomistic dynamics in proteins and other biomolecules at the single molecule level. At such short wavelengths the X-ray photons will eject electrons from the sample. This will lead to a coulomb explosion of the nuclei. Thus it is crucial how much time-resolved structural information can be expected from a single molecule diffraction experiment. To address this question, we have begun to develop a method to simulate the electronic response of biomolecular systems subject to electron emission. Due to their strong binding to the nuclei, the inner shell electrons show significantly larger X-ray cross section than the outer electrons, such that the initial event will be the nearly instantaneous partial removal of the inner shells. The resulting fast re-filling dynamics by electrons of the outer shells will critically determine the atomic dynamics and the pace of the Coulomb explosion.In our simulations, a stochastic criterion is used to generate an initial open shell system based on the cross sections. We use Hartree-Fock level of theory and gaussian basis sets to treat the initial state. The expansion coefficients of the basis functions are taken to be time-dependent. Thus the expansion coefficients are propagated by the time-dependent Schroedinger equation. This time-dependent approach is currently applied to a one dimensional model system. We plan to apply it to real molecular systems. Our goal is to treat systems up to the size of a peptide.[1] R. Neutze, et. al., “Potential for biomolecular imaging with femtosecond X-ray pulses”, Nature, 406, 752 (2000).