Learning Force Field Parameters from Differentiable Particle-Field Molecular Dynamics.

We develop ∂-HylleraasMD (∂-HyMD), a fully end-to-end differentiable molecular dynamics software based on the Hamiltonian hybrid particle-field formalism, and use it to establish a protocol for automated optimization of force field parameters. ∂-HyMD is templated on the recently released HylleraaasMD software, while using the JAX autodiff framework as the main engine for the differentiable dynamics. ∂-HyMD exploits an embarrassingly parallel optimization algorithm by spawning independent simulations, whose trajectories are simultaneously processed by reverse mode automatic differentiation to calculate the gradient of the loss function, which is in turn used for iterative optimization of the force-field parameters. We show that parallel organization facilitates the convergence of the minimization procedure, avoiding the known memory and numerical stability issues of differentiable molecular dynamics approaches. We showcase the effectiveness of our implementation by producing a library of force field parameters for standard phospholipids, with either zwitterionic or anionic heads and with saturated or unsaturated tails. Compared to the all-atom reference, the force field obtained by ∂-HyMD yields better density profiles than the parameters derived from previously utilized gradient-free optimization procedures. Moreover, ∂-HyMD models can predict with good accuracy properties not included in the learning objective, such as lateral pressure profiles, and are transferable to other systems, including triglycerides.

Time-resolved THz Stark spectroscopy of molecules in solution.

For decades, it was considered all but impossible to perform Stark spectroscopy on molecules in a liquid solution, because their concomitant orientation to the applied electric field results in overwhelming background signals. A way out was to immobilize the solute molecules by freezing the solvent. While mitigating solute orientation, freezing removes the possibility to study molecules in liquid environments at ambient conditions. Here we demonstrate time-resolved THz Stark spectroscopy, utilizing intense single-cycle terahertz pulses as electric field source. At THz frequencies, solute molecules have no time to orient their dipole moments. Hence, dynamic Stark spectroscopy on the time scales of molecular vibrations or rotations in both non-polar and polar solvents at arbitrary temperatures is now possible. We verify THz Stark spectroscopy for two judiciously selected molecular systems and compare the results to conventional Stark spectroscopy and first principle calculations.

Electron population dynamics in resonant non-linear x-ray absorption in nickel at a free-electron laser.

Free-electron lasers provide bright, ultrashort, and monochromatic x-ray pulses, enabling novel spectroscopic measurements not only with femtosecond temporal resolution: The high fluence of their x-ray pulses can also easily enter the regime of the non-linear x-ray-matter interaction. Entering this regime necessitates a rigorous analysis and reliable prediction of the relevant non-linear processes for future experiment designs. Here, we show non-linear changes in the L3-edge absorption of metallic nickel thin films, measured with fluences up to 60 J/cm2. We present a simple but predictive rate model that quantitatively describes spectral changes based on the evolution of electronic populations within the pulse duration. Despite its simplicity, the model reaches good agreement with experimental results over more than three orders of magnitude in fluence, while providing a straightforward understanding of the interplay of physical processes driving the non-linear changes. Our findings provide important insights for the design and evaluation of future high-fluence free-electron laser experiments and contribute to the understanding of non-linear electron dynamics in x-ray absorption processes in solids at the femtosecond timescale.

Fast, automated, continuous energy scans for experimental phasing at the BioMAX beamline.

In X-ray macromolecular crystallography (MX), single-wavelength anomalous dispersion (SAD) and multi-wavelength anomalous dispersion (MAD) techniques are commonly used for obtaining experimental phases. For an MX synchrotron beamline to support SAD and MAD techniques it is a prerequisite to have a reliable, fast and well automated energy scan routine. This work reports on a continuous energy scan procedure newly implemented at the BioMAX MX beamline at MAX IV Laboratory. The continuous energy scan is fully automated, capable of measuring accurate fluorescence counts over the absorption edge of interest while minimizing the sample exposure to X-rays, and is about a factor of five faster compared with a conventional step scan previously operational at BioMAX. The implementation of the continuous energy scan facilitates the prompt access to the anomalous scattering data, required for the SAD and MAD experiments.

SANS Spectra with PLUMED: Implementation and Application to Metainference.

Using small-angle scattering with either X-ray or neutron sources has become common in the investigation of soft-matter systems. These experiments provide information about the coarse shape of the scattered objects, but obtaining more-detailed information can usually only be achieved with the aid of molecular simulations. In this Application Note, we report the implementation of an extension in PLUMED to compute the small-angle neutron scattering (SANS), which can be used for data processing as well for enhanced sampling, in particular with the metainference method to bias simulations and sample structures with a resulting spectrum in agreement with an experimental reference. Our implementation includes a resolution function that can be used to smear the SANS intensities according to beamline error sources and is compatible with both all-atom and coarse-grained simulations. Scripts to aid in the calculation of the scattering lengths when the system is coarse-grained and to aid in preparing the inputs are provided. We illustrate the use of the implementation with metainference by performing coarse-grained simulations of beta-octylglucoside and dodecylphosphocholine micelles in water. With different software and different Hamiltonians, we show that the metainference SANS bias can drive micelles to be split and to change shapes to achieve a better agreement with the experimental reference.

Morphological Plasticity of LiCl Clusters Interacting with Grignard Reagent in Tetrahydrofuran.

Ab initio molecular dynamics simulations are used to explore tetrahydrofuran (THF) solutions containing pure LiCl and LiCl with CH3MgCl, as model constituents of the turbo Grignard reagent. LiCl aggregates as Li4Cl4, which preferentially assumes compact cubane-like conformations. In particular, an open-edge pseudotetrahedral frame is promoted by solvent-assisted Li-Cl bond cleavage. Among the Grignard species involved in the Schlenk equilibrium, LiCl prefers to coordinate MgCl2 through µ2-Cl bridges. Using a 1:1 Li:Mg ratio, the plastic tetranuclear LiCl cluster decomposes to a highly solvated mixed LiCl·MgCl2 aggregate with prevalent Li-(µ2-Cl)2-Mg rings and linear LiCl entities. The MgCl2-assisted disaggregation of Li4Cl4 occurs through transient structures analogous to those detected for pure LiCl in THF, also corresponding to moieties observed in the solid state. This study identifies a synergistic role of LiCl for the determination of the compounds present in turbo Grignard solutions. LiCl shifts the Schlenk equilibrium promoting a higher concentration of dialkylmagnesium, while decomposing into smaller, more soluble, mixed Li:Mg:Cl clusters.

Accelerating Lipid Flip-Flop at Low Concentrations: A General Mechanism for Membrane Binding Peptides.

We report a physicochemical investigation of the lipid transport properties of model lipid membranes in the presence of the antimicrobial peptide indolicidin through comparisons of experimental SANS/SAXS scattering techniques to fully atomistic molecular dynamics simulations. In agreement with the experiment, we show that upon peripheral binding of the peptides, even at low concentrations, lipid flip-flop dynamics is greatly accelerated. Computer modeling elucidates the interplay between structural changes and lipid dynamics induced by peptides and proposes a mechanism for the mode of action of antimicrobial peptides, assessing the major role of entropy for the catalysis of the flipping events. The mechanism introduced here is universal for all peptides with preferential peripheral binding to the membrane as it does not depend on the specific amino acid sequence.

HylleraasMD: A Domain Decomposition-Based Hybrid Particle-Field Software for Multiscale Simulations of Soft Matter.

We present HylleraasMD (HyMD), a comprehensive implementation of the recently proposed Hamiltonian formulation of hybrid particle-field molecular dynamics. The methodology is based on a tunable, grid-independent length-scale of coarse graining, obtained by filtering particle densities in reciprocal space. This enables systematic convergence of energies and forces by grid refinement, also eliminating nonphysical force aliasing. Separating the time integration of fast modes associated with internal molecular motion from slow modes associated with their density fields, we enable the first time-reversible, energy-conserving hybrid particle-field simulations. HyMD comprises the optional use of explicit electrostatics, which, in this formalism, corresponds to the long-range potential in particle-mesh Ewald. We demonstrate the ability of HyMD to perform simulations in the microcanonical and canonical ensembles with a series of test cases, comprising lipid bilayers and vesicles, surfactant micelles, and polypeptide chains, comparing our results to established literature. An on-the-fly increase of the characteristic coarse-grain length significantly speeds up dynamics, accelerating self-diffusion and leading to expedited aggregation. Exploiting this acceleration, we find that the time scales involved in the self-assembly of polymeric structures can lie in the tens to hundreds of picoseconds instead of the multimicrosecond regime observed with comparable coarse-grained models.

Micelle kinetics of photoswitchable surfactants: Self-assembly pathways and relaxation mechanisms.

HYPOTHESIS: A key question in the kinetics of surfactant self-assembly is whether exchange of unimers or fusion/fission of entire micelles is the dominant pathway. In this study, an isomerizable surfactant is used to explore fundamental out-of-equilibrium kinetics and mechanisms for growth and dissolution of micelles. EXPERIMENTS: The kinetics of cationic surfactant 4-butyl-4'-(3-trimethylammoniumpropoxy)-phenylazobenzene was studied using molecular dynamics simulations. The fusion and exchange processes were investigated using umbrella sampling. Equilibrium states were validated by comparison with small-angle X-ray scattering data. The photo-isomerization event was simulated by modifying the torsion potential of the photo-responsive group to emulate the trans-to-cis transition. FINDINGS: Micelle growth is dominated by unimer exchange processes, whereas, depending on the conditions, dissolution can occur both through fission and unimer expulsion. Fusion barriers increase steeply with the aggregation number making this an unlikely pathway to equilibrium for micelles of sizes that fit with the experimental data. The barriers for unimer expulsion remain constant and are much lower for unimer insertion, making exchange more likely at high aggregation. When simulating photo-conversion events, both fission and a large degree of unimer expulsion can occur depending on the extent of the out-of-equilibrium stress that is put on the system.

On the equivalence of the hybrid particle-field and Gaussian core models.

Hybrid particle-field molecular dynamics is a molecular simulation strategy, wherein particles couple to a density field instead of through ordinary pair potentials. Traditionally considered a mean-field theory, a momentum and energy-conserving hybrid particle-field formalism has recently been introduced, which was demonstrated to approach the Gaussian Core model potential in the grid-converged limit. Here, we expand on and generalize the correspondence between the Hamiltonian hybrid particle-field method and particle-particle pair potentials. Using the spectral procedure suggested by Bore and Cascella, we establish compatibility to any local soft pair potential in the limit of infinitesimal grid spacing. Furthermore, we document how the mean-field regime often observed in hybrid particle-field simulations is due to the systems under consideration, and not an inherent property of the model. Considering the Gaussian filter form, in particular, we demonstrate the ability of the Hamiltonian hybrid particle-field model to recover all structural and dynamical properties of the Gaussian Core model, including solid phases, a first-order phase transition, and anomalous transport properties. We quantify the impact of the grid spacing on the correspondence, as well as the effect of the particle-field filtering length scale on the emergent particle-particle correlations.

The structural basis of the multi-step allosteric activation of Aurora B kinase.

Aurora B, together with IN-box, the C-terminal part of INCENP, forms an enzymatic complex that ensures faithful cell division. The [Aurora B/IN-box] complex is activated by autophosphorylation in the Aurora B activation loop and in IN-box, but it is not clear how these phosphorylations activate the enzyme. We used a combination of experimental and computational studies to investigate the effects of phosphorylation on the molecular dynamics and structure of [Aurora B/IN-box]. In addition, we generated partially phosphorylated intermediates to analyze the contribution of each phosphorylation independently. We found that the dynamics of Aurora and IN-box are interconnected, and IN-box plays both positive and negative regulatory roles depending on the phosphorylation status of the enzyme complex. Phosphorylation in the activation loop of Aurora B occurs intramolecularly and prepares the enzyme complex for activation, but two phosphorylated sites are synergistically responsible for full enzyme activity.

Soft Matter under Pressure: Pushing Particle-Field Molecular Dynamics to the Isobaric Ensemble.

Hamiltonian hybrid particle-field molecular dynamics is a computationally efficient method to study large soft matter systems. In this work, we extend this approach to constant-pressure (NPT) simulations. We reformulate the calculation of internal pressure from the density field by taking into account the intrinsic spread of the particles in space, which naturally leads to a direct anisotropy in the pressure tensor. The anisotropic contribution is crucial for reliably describing the physics of systems under pressure, as demonstrated by a series of tests on analytical and monatomic model systems as well as realistic water/lipid biphasic systems. Using Bayesian optimization, we parametrize the field interactions of phospholipids to reproduce the structural properties of their lamellar phases, including area per lipid, and local density profiles. The resulting model excels in providing pressure profiles in qualitative agreement with all-atom modeling, and surface tension and area compressibility in quantitative agreement with experimental values, indicating the correct description of long-wavelength undulations in large membranes. Finally, we demonstrate that the model is capable of reproducing the formation of lipid droplets inside a lipid bilayer.

Solid-State 19F NMR Chemical Shift in Square-Planar Nickel-Fluoride Complexes Linked by Halogen Bonds.

The halogen bond (XB) is a highly directional class of noncovalent interactions widely explored by experimental and computational studies. However, the NMR signature of the XB has attracted limited attention. The prediction and analysis of the solid-state NMR (SSNMR) chemical shift tensor provide useful strategies to better understand XB interactions. In this work, we employ a computational protocol for modeling and analyzing the 19F SSNMR chemical shifts previously measured in a family of square-planar trans NiII-L2-iodoaryl-fluoride (L = PEt3) complexes capable of forming self-complementary networks held by a NiF···I(C) halogen bond [Thangavadivale, V.; Chem. Sci. 2018, 9, 3767-3781]. To understand how the 19F NMR resonances of the nickel-bonded fluoride are affected by the XB, we investigate the origin of the shielding in trans-[NiF(2,3,5,6-C6F4I)(PEt3)2], trans-[NiF(2,3,4,5-C6F4I)(PEt3)2], and trans-[NiF(C6F5)(PEt3)2] in the solid state, where a XB is present in the two former systems but not in the last. We perform the 19F NMR chemical shift calculations both in periodic and molecular models. The results show that the crystal packing has little influence on the NMR signatures of the XB, and the NMR can be modeled successfully with a pair of molecules interacting via the XB. Thus, the observed difference in chemical shift between solid-state and solution NMR can be essentially attributed to the XB interaction. The very high shielding of the fluoride and its driving contributor, the most shielded component of the chemical shift tensor, are well reproduced at the 2c-ZORA level. Analysis of the factors controlling the shielding shows how the highest occupied Ni/F orbitals shield the fluoride in the directions perpendicular to the Ni-F bond and specifically perpendicular to the coordination plane. This shielding arises from the magnetic coupling of the Ni(3d)/F(2p lone pair) orbitals with the vacant σNi-F* orbital, thereby rationalizing the very highly upfield (shielded) resonance of the component (δ33) along this direction. We show that these features are characteristic of square-planar nickel-fluoride complexes. The deshielding of the fluoride in the halogen-bonded systems is attributed to an increase in the energy gap between the occupied and vacant orbitals that are mostly responsible for the paramagnetic terms, notably along the most shielded direction.

What Drives Chorismate Mutase to Top Performance? Insights from a Combined In Silico and In Vitro Study.

Unlike typical chorismate mutases, the enzyme from Mycobacterium tuberculosis (MtCM) has only low activity on its own. Remarkably, its catalytic efficiency kcat/Km can be boosted more than 100-fold by complex formation with a partner enzyme. Recently, an autonomously fully active MtCM variant was generated using directed evolution, and its structure was solved by X-ray crystallography. However, key residues were involved in crystal contacts, challenging the functional interpretation of the structural changes. Here, we address these challenges by microsecond molecular dynamics simulations, followed up by additional kinetic and structural analyses of selected sets of specifically engineered enzyme variants. A comparison of wild-type MtCM with naturally and artificially activated MtCMs revealed the overall dynamic profiles of these enzymes as well as key interactions between the C-terminus and the active site loop. In the artificially evolved variant of this model enzyme, this loop is preorganized and stabilized by Pro52 and Asp55, two highly conserved residues in typical, highly active chorismate mutases. Asp55 stretches across the active site and helps to appropriately position active site residues Arg18 and Arg46 for catalysis. The role of Asp55 can be taken over by another acidic residue, if introduced at position 88 close to the C-terminus of MtCM, as suggested by molecular dynamics simulations and confirmed by kinetic investigations of engineered variants.

Real-time spatial characterization of micrometer-sized X-ray free-electron laser beams focused by bendable mirrors.

A real-time and accurate characterization of the X-ray beam size is essential to enable a large variety of different experiments at free-electron laser facilities. Typically, ablative imprints are employed to determine shape and size of µm-focused X-ray beams. The high accuracy of this state-of-the-art method comes at the expense of the time required to perform an ex-situ image analysis. In contrast, diffraction at a curved grating with suitably varying period and orientation forms a magnified image of the X-ray beam, which can be recorded by a 2D pixelated detector providing beam size and pointing jitter in real time. In this manuscript, we compare results obtained with both techniques, address their advantages and limitations, and demonstrate their excellent agreement. We present an extensive characterization of the FEL beam focused to ≈1 µm by two Kirkpatrick-Baez (KB) mirrors, along with optical metrology slope profiles demonstrating their exceptionally high quality. This work provides a systematic and comprehensive study of the accuracy provided by curved gratings in real-time imaging of X-ray beams at a free-electron laser facility. It is applied here to soft X-rays and can be extended to the hard X-ray range. Furthermore, curved gratings, in combination with a suitable detector, can provide spatial properties of µm-focused X-ray beams at MHz repetition rate.

Bias Amplification in Gender, Gender Identity, and Geographical Affiliation.

In the quest for greater equity in science, individual attitudes and institutional policies should also embrace greater diversity and inclusion of minority groups. This viewpoint calls for a broader definition of gender bias in STEM to include gender identity and for increased attention to the issue of bias amplification due to geographic affiliation in the field of computational chemistry and chemoinformatics. It briefly discusses some active interventions to tackle bias on gender, gender identity, and geographic affiliation in STEM.

Wavefunction-Based Electrostatic-Embedding QM/MM Using CFOUR through MiMiC.

We present an interface of the wavefunction-based quantum chemical software CFOUR to the multiscale modeling framework MiMiC. Electrostatic embedding of the quantum mechanical (QM) part is achieved by analytic evaluation of one-electron integrals in CFOUR, while the rest of the QM/molecular mechanical (MM) operations are treated according to the previous MiMiC-based QM/MM implementation. Long-range electrostatic interactions are treated by a multipole expansion of the potential from the QM electron density to reduce the computational cost without loss of accuracy. Testing on model water/water systems, we verified that the CFOUR interface to MiMiC is robust, guaranteeing fast convergence of the self-consistent field cycles and optimal conservation of the energy during the integration of the equations of motion. Finally, we verified that the CFOUR interface to MiMiC is compatible with the use of a QM/QM multiple time-step algorithm, which effectively reduces the cost of ab initio MD (AIMD) or QM/MM-MD simulations using higher level wavefunction-based approaches compared to cheaper density functional theory-based ones. The new wavefunction-based AIMD and QM/MM-MD implementations were tested and validated for a large number of wavefunction approaches, including Hartree-Fock and post-Hartree-Fock methods like Møller-Plesset, coupled-cluster, and complete active space self-consistent field.

Aggregation of Lipid A Variants: A Hybrid Particle-Field Model.

Lipid A is one of the three components of bacterial lipopolysaccharides constituting the outer membrane of Gram-negative bacteria, and is recognized to have an important biological role in the inflammatory response of mammalians. Its biological activity is modulated by the number of acyl-chains that are present in the lipid and by the dielectric medium, i.e., the type of counter-ions, through electrostatic interactions. In this paper, we report on a coarse-grained model of chemical variants of Lipid A based on the hybrid particle-field/molecular dynamics approach (hPF-MD). In particular, we investigate the stability of Lipid A bilayers for two different hexa- and tetra-acylated structures. Comparing particle density profiles along bilayer cross-sections, we find good agreement between the hPF-MD model and reference all-atom simulation for both chemical variants of Lipid A. hPF-MD models of constituted bilayers composed by hexa-acylated Lipid A in water are stable within the simulation time. We further validate our model by verifying that the phase behavior of Lipid A/counterion/water mixtures is correctly reproduced. In particular, hPF-MD simulations predict the correct self-assembly of different lamellar and micellar phases from an initially random distribution of Lipid A molecules with counterions in water. Finally, it is possible to observe the spontaneous formation and stability of Lipid A vesicles by fusion of micellar aggregates.

Engineering of a functional γ-tocopherol transfer protein.

α-tocopherol transfer protein (TTP) was previously reported to self-aggregate into 24-meric spheres (α-TTPS) and to possess transcytotic potency across mono-layers of human umbilical vein endothelial cells (HUVECs). In this work, we describe the characterisation of a functional TTP variant with its vitamer selectivity shifted towards γ-tocopherol. The shift was obtained by introducing an alanine to leucine substitution into the substrate-binding pocket at position 156 through site directed mutagenesis. We report here the X-ray crystal structure of the γ-tocopherol specific particle (γ-TTPS) at 2.24 Å resolution. γ-TTPS features full functionality compared to its α-tocopherol specific parent including self-aggregation potency and transcytotic activity in trans-well experiments using primary HUVEC cells. The impact of the A156L mutation on TTP function is quantified in vitro by measuring the affinity towards γ-tocopherol through micro-differential scanning calorimetry and by determining its ligand-transfer activity. Finally, cell culture experiments using adherently grown HUVEC cells indicate that the protomers of γ-TTP, in contrast to α-TTP, do not counteract cytokine-mediated inflammation at a transcriptional level. Our results suggest that the A156L substitution in TTP is fully functional and has the potential to pave the way for further experiments towards the understanding of α-tocopherol homeostasis in humans.

First-Principles Calculation of 1H NMR Chemical Shifts of Complex Metal Polyhydrides: The Essential Inclusion of Relativity and Dynamics.

1H NMR spectroscopy has become an important technique for the characterization of transition-metal hydride complexes, whose metal-bound hydrides are often difficult to locate by X-ray diffraction. In this regard, the accurate prediction of 1H NMR chemical shifts provides a useful, but challenging, strategy to help in the interpretation of the experimental spectra. In this work, we establish a density-functional-theory protocol that includes relativistic, solvent, and dynamic effects at a high level of theory, allowing us to report an accurate and reliable interpretation of 1H NMR hydride chemical shifts of iridium polyhydride complexes. In particular, we have studied in detail the hydride chemical shifts of the [Ir6(IMe)8(CO)2H14]2+ complex in order to validate previous assignments. The computed 1H NMR chemical shifts are strongly dependent on the relativistic treatment, the choice of the DFT exchange-correlation functional, and the conformational dynamics. By combining a fully relativistic four-component electronic-structure treatment with ab initio molecular dynamics, we were able to reliably model both the terminal and bridging hydride chemical shifts and to show that two NMR hydride signals were inversely assigned in the experiment.