Beyond isotropic repulsion: Classical anisotropic repulsion by inclusion of p orbitals.

Accurate modeling of intermolecular repulsion is an integral component in force field development. Although repulsion can be explicitly calculated by applying the Pauli exclusion principle, this approach is computationally viable only for systems of limited sizes. Instead, it has previously been shown that repulsion can be reformulated in a "classical" picture: the Pauli exclusion principle prohibits electrons from occupying the same state, leading to a depletion of electronic charge between atoms, giving rise to an enhanced nuclear-nuclear electrostatic repulsion. This classical picture is called the isotropic S2/R approximation, where S is the overlap and R is the interatomic distance. This approximation accurately captures the repulsion of isotropic atoms such as noble gas dimers; however, a key deficiency is that it fails to capture the angular dependence of the repulsion of anisotropic molecules. To include directionality, the wave function must at least be a linear combination of s and p orbitals. We derive a new anisotropic S2/R repulsion model through the inclusion of the anisotropic p orbital term in the total wave function. Because repulsion is pairwise and decays rapidly, it can be truncated at a short range, making it amenable for efficient calculation of energy and forces in complex biomolecular systems. We present a parameterization of the S101 dimer database against the ab initio benchmark symmetry-adapted perturbation theory, which yields an rms error of only 0.9 kcal/mol. The importance of the anisotropic term is demonstrated through angular scans of water-water dimers and dimers involving halobenzene. Simulation of liquid water shows that the model can be computed efficiently for realistic system sizes.

A new method to calculate broadband dielectric spectra of solvents from molecular dynamics simulations demonstrated with polarizable force fields.

Simulating the dielectric spectra of solvents requires the nuanced definition of inter- and intra-molecular forces. Non-polarizable force fields, while thoroughly benchmarked for dielectric applications, do not capture all the spectral features of solvents, such as water. Conversely, polarizable force fields have been largely untested in the context of dielectric spectroscopy but include charge and dipole fluctuations that contribute to intermolecular interactions. We benchmark non-polarizable force fields and the polarizable force fields AMOEBA03 and HIPPO for liquid water and find that the polarizable force fields can capture all the experimentally observed spectral features with varying degrees of accuracy. However, the non-polarizable force fields miss at least one peak. To diagnose this deficiency, we decompose the liquid water spectra from polarizable force fields at multiple temperatures into static and induced dipole contributions and find that the peak originates from induced dipole contributions. Broadening our inquiry to other solvents parameterized with the AMOEBA09 force field, we demonstrate good agreement between the experimental and simulated dielectric spectra of methanol and formamide. To produce these spectra, we develop a new computational approach to calculate the dielectric spectrum via the fluctuation dissipation theorem. This method minimizes the error in both the low and high frequency portions of the spectrum, improving the overall accuracy of the simulated spectrum and broadening the computed frequency range.

Accurate Host-Guest Binding Free Energies Using the AMOEBA Polarizable Force Field.

A grand challenge of computational biophysics is accurate prediction of interactions between molecules. Molecular dynamics (MD) simulations have recently gained much interest as a tool to directly compute rigorous intermolecular binding affinities. The choice of a fixed point-charge or polarizable multipole force field used in MD is a topic of ongoing discussion. To compare alternative methods, we participated in the SAMPL7 and SAMPL8 Gibb octaacid host-guest challenges to assess the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) polarizable multipole force field. Advantages of AMOEBA over fixed charge models include improved representation of molecular electrostatic potentials and better description of water occupying the unligated host cavity. Prospective predictions for 26 host-guest systems exhibit a mean unsigned error vs experiment of 0.848 kcal/mol across all absolute binding free energies, demonstrating excellent agreement between computational and experimental results. In addition, we explore two topics related to the inclusion of ions in MD simulations: use of a neutral co-alchemical protocol and the effect of salt concentration on binding affinity. Use of the co-alchemical method minimally affects computed energies, but salt concentration significantly perturbs our binding results. Higher salt concentration strengthens binding through classical charge screening. In particular, added Na+ ions screen negatively charged carboxylate groups near the binding cavity, thereby diminishing repulsive coulomb interactions with negatively charged guests. Overall, the AMOEBA results demonstrate the accuracy available through a force field providing a detailed energetic description of the four octaacid hosts and 13 charged organic guests. Use of the AMOEBA polarizable atomic multipole force field in conjunction with an alchemical free energy protocol can achieve chemical accuracy in application to realistic molecular systems.

Experimental Demonstration of Double Emittance Exchange toward Arbitrary Longitudinal Beam Phase-Space Manipulations.

Many of the most significant advances in accelerator science have been due to improvements in our ability to manipulate beam phase space. Despite steady progress in beam phase-space manipulation over the last several decades, future accelerator applications continue to outpace the ability to manipulate the phase space. This situation is especially pronounced for longitudinal beam phase-space manipulation, and is now getting increased attention. Herein, we report the first experimental demonstration of the double emittance exchange concept, which allows for the control of the longitudinal phase space using relatively simple transverse manipulation techniques. The double emittance exchange beamline enables extensive longitudinal manipulation, including tunable bunch compression, time-energy correlation control, and nonlinearity correction, in a remarkably flexible manner. The demonstration of this new method opens the door for arbitrary longitudinal beam manipulations capable of responding to the ever increasing demands of future accelerator applications.

High Resolution Photoexcitation Measurements Exacerbate the Long-Standing Fe XVII Oscillator Strength Problem.

For more than 40 years, most astrophysical observations and laboratory studies of two key soft x-ray diagnostic 2p-3d transitions, 3C and 3D, in Fe XVII ions found oscillator strength ratios f(3C)/f(3D) disagreeing with theory, but uncertainties had precluded definitive statements on this much studied conundrum. Here, we resonantly excite these lines using synchrotron radiation at PETRA III, and reach, at a millionfold lower photon intensities, a 10 times higher spectral resolution, and 3 times smaller uncertainty than earlier work. Our final result of f(3C)/f(3D)=3.09(8)(6) supports many of the earlier clean astrophysical and laboratory observations, while departing by five sigmas from our own newest large-scale ab initio calculations, and excluding all proposed explanations, including those invoking nonlinear effects and population transfers.

Generalized Kapchinskij-Vladimirskij Distribution and Beam Matrix for Phase-Space Manipulations of High-Intensity Beams.

In an uncoupled linear lattice system, the Kapchinskij-Vladimirskij (KV) distribution formulated on the basis of the single-particle Courant-Snyder invariants has served as a fundamental theoretical basis for the analyses of the equilibrium, stability, and transport properties of high-intensity beams for the past several decades. Recent applications of high-intensity beams, however, require beam phase-space manipulations by intentionally introducing strong coupling. In this Letter, we report the full generalization of the KV model by including all of the linear (both external and space-charge) coupling forces, beam energy variations, and arbitrary emittance partition, which all form essential elements for phase-space manipulations. The new generalized KV model yields spatially uniform density profiles and corresponding linear self-field forces as desired. The corresponding matrix envelope equations and beam matrix for the generalized KV model provide important new theoretical tools for the detailed design and analysis of high-intensity beam manipulations, for which previous theoretical models are not easily applicable.

Generalized Courant-Snyder theory for charged-particle dynamics in general focusing lattices.

The Courant-Snyder (CS) theory for one degree of freedom is generalized to the case of coupled transverse dynamics in general linear focusing lattices with quadrupole, skew-quadrupole, dipole, and solenoidal components, as well as torsion of the fiducial orbit and variation of beam energy. The envelope function is generalized into an envelope matrix, and the phase advance is generalized into a 4D sympletic rotation. The envelope equation, the transfer matrix, and the CS invariant of the original CS theory all have their counterparts, with remarkably similar expressions, in the generalized theory.

Classical Exchange Polarization: An Anisotropic Variable Polarizability Model.

Polarizability, or the tendency of the electron distribution to distort under an electric field, often depends on the local chemical environment. For example, the polarizability of a chloride ion is larger in gas phase compared to a chloride ion solvated in water. This effect is due to the restriction the Pauli exclusion principle places on the allowed electron states. Because no two electrons can occupy the same state, when a highly polarizable atom comes in close contact with other atoms or molecules, the space of allowed states can dramatically decrease. This constraint suggests that an accurate molecular mechanics polarizability model should depend on the radial distance between neighboring atoms. This paper introduces a variable polarizability model within the framework of the HIPPO (Hydrogen-like Intermolecular Polarizable Potential) force field, by damping the polarizability as a function of the orbital overlap of two atoms. This effectively captures the quantum mechanical exchange polarization effects, without explicit utilization of antisymmetrized wave functions. We show that the variable polarizability model remarkably improves the two-body polarization energies and three-body energies of ion-ion and ion-water systems. Under this model, no manual tuning of atomic polarizabilities for monatomic ions is required; the gas-phase polarizability can be used because an appropriate damping function is able to correct the polarizability at short range.

Deep learning the structural determinants of protein biochemical properties by comparing structural ensembles with DiffNets.

Understanding the structural determinants of a protein's biochemical properties, such as activity and stability, is a major challenge in biology and medicine. Comparing computer simulations of protein variants with different biochemical properties is an increasingly powerful means to drive progress. However, success often hinges on dimensionality reduction algorithms for simplifying the complex ensemble of structures each variant adopts. Unfortunately, common algorithms rely on potentially misleading assumptions about what structural features are important, such as emphasizing larger geometric changes over smaller ones. Here we present DiffNets, self-supervised autoencoders that avoid such assumptions, and automatically identify the relevant features, by requiring that the low-dimensional representations they learn are sufficient to predict the biochemical differences between protein variants. For example, DiffNets automatically identify subtle structural signatures that predict the relative stabilities of ß-lactamase variants and duty ratios of myosin isoforms. DiffNets should also be applicable to understanding other perturbations, such as ligand binding.

Stand-off radiation detection techniques.

Remote detection of radioactive materials is extremely challenging, yet it is important to realize the technique for safe usage of radioactive materials. Gamma rays are the most far distant penetrating photons that are involved with the radiation decay process. Herein, we overview the gamma-ray detection techniques that are material-based and vacuum tube-based. A muon detector is also reviewed as a radioactive material imager. We overview versatile detectors that are currently being widely used and new concepts that may pave the way for promising remote detectability up to several kilometers.

Generalized Kapchinskij-Vladimirskij distribution and envelope equation for high-intensity beams in a coupled transverse focusing lattice.

In an uncoupled lattice, the Kapchinskij-Vladimirskij (KV) distribution function first analyzed in 1959 is the only known exact solution of the nonlinear Vlasov-Maxwell equations for high-intensity beams including self-fields in a self-consistent manner. The KV solution is generalized here to high-intensity beams in a coupled transverse lattice using the recently developed generalized Courant-Snyder invariant for coupled transverse dynamics. This solution projects to a rotating, pulsating elliptical beam in transverse configuration space, determined by the generalized matrix envelope equation.

Carbonic anhydrase II microcrystals suitable for XFEL studies.

Recent advances in X-ray free-electron laser (XFEL) sources have permitted the study of protein dynamics. Femtosecond X-ray pulses have allowed the visualization of intermediate states in enzyme catalysis. In this study, the growth of carbonic anhydrase II microcrystals (40-80 µm in length) suitable for the collection of XFEL diffraction data at the Pohang Accelerator Laboratory is demonstrated. The crystals diffracted to 1.7 Šresolution and were indexed in space group P21, with unit-cell parameters a = 42.2, b = 41.2, c = 72.0 Å, ß = 104.2°. These preliminary results provide the necessary framework for time-resolved experiments to study carbonic anhydrase catalysis at XFEL beamlines.

Use of a linear Paul trap to study random noise-induced beam degradation in high-intensity accelerators.

A random noise-induced beam degradation that can affect intense beam transport over long propagation distances has been experimentally studied by making use of the transverse beam dynamics equivalence between an alternating-gradient (AG) focusing system and a linear Paul trap system. For the present studies, machine imperfections in the quadrupole focusing lattice are considered, which are emulated by adding small random noise on the voltage waveform of the quadrupole electrodes in the Paul trap. It is observed that externally driven noise continuously produces a nonthermal tail of trapped ions, and increases the transverse emittance almost linearly with the duration of the noise.