Structural biology in the age of X-ray free-electron lasers and exascale computing.

Serial femtosecond X-ray crystallography has emerged as a powerful method for investigating biomolecular structure and dynamics. With the new generation of X-ray free-electron lasers, which generate ultrabright X-ray pulses at megahertz repetition rates, we can now rapidly probe ultrafast conformational changes and charge movement in biomolecules. Over the last year, another innovation has been the deployment of Frontier, the world's first exascale supercomputer. Synergizing extremely high repetition rate X-ray light sources and exascale computing has the potential to accelerate discovery in biomolecular sciences. Here we outline our perspective on each of these remarkable innovations individually, and the opportunities and challenges in yoking them within an integrated research infrastructure.

All-Atom Biomolecular Simulation in the Exascale Era.

Exascale supercomputers have opened the door to dynamic simulations, facilitated by AI/ML techniques, that model biomolecular motions over unprecedented length and time scales. This new capability holds the potential to revolutionize our understanding of fundamental biological processes. Here we report on some of the major advances that were discussed at a recent CECAM workshop in Pisa, Italy, on the topic with a primary focus on atomic-level simulations. First, we highlight examples of current large-scale biomolecular simulations and the future possibilities enabled by crossing the exascale threshold. Next, we discuss challenges to be overcome in optimizing the usage of these powerful resources. Finally, we close by listing several grand challenge problems that could be investigated with this new computer architecture.

MD Simulation of Water Using a Rigid Body Description Requires a Small Time Step to Ensure Equipartition.

In simulations of aqueous systems, it is common to freeze the bond vibration and angle bending modes in water to allow for a longer time step δt for integrating the equations of motion. Thus, δt = 2 fs is often used in simulating rigid models of water. We simulate the SPC/E model of water using δt from 0.5 to 3.0 fs and up to 4 fs using hydrogen mass repartitioning. In these simulations, we find that for all but δt = 0.5 fs, equipartition is not obtained between translational and rotational modes, with the rotational modes exhibiting a lower temperature than the translation modes. To probe the reasons for the lack of equipartition, we study the autocorrelation of the translational velocity of the center of mass and the angular velocity of the rigid water molecule, respectively. We find that the rotational relaxation occurs on a timescale comparable to vibrational periods, calling into question the original motivations for freezing the vibrations. Furthermore, a time step with δt ≥ 1 fs is not able to capture accurately the fast rotational relaxation, which reveals its impact as an effective slowing-down of rotational relaxation. The fluctuation-dissipation relation then leads to the conclusion that the rotational temperature should be cooler for δt greater than the reference value of 0.5 fs. Consideration of fluctuation-dissipation in equilibrium molecular dynamics simulations also emphasizes the need to capture the temporal evolution of fluctuations with fidelity and the role of δt in this regard. The time step also influences the solution thermodynamic properties: both the mean system potential energies and the excess entropy of hydration of a soft repulsive cavity are sensitive to δt.

A novel inclusion complex of oxybenzone with C-methylresorcin[4]arene deters skin permeation.

Oxybenzone (OXB), a very widely used sunscreen ingredient has the potential to block both UVA and UVB but can penetrate through skin. Studies have revealed its presence in the blood and urine of most humans, which may lead to long-term health effects. As the confined cavities of macrocycles can alter the physical and chemical properties of encapsulated guests, in this study, we investigated the formation of host-guest complexes between C-methylresorcin[4]arene and OXB. Combined experimental (NMR spectroscopy, UV/vis absorption, and fluorescence spectroscopy) and theoretical investigation confirmed the formation of a weak host-guest complex that had a 1 : 1 stoichiometry. Furthermore, skin permeation testing revealed that complexation by C-methylresorcin[4]arene significantly reduced the skin permeation of OXB which can potentially limit the harmful effects of this organic sunscreen.

Assessment of a host-guest interaction in a bilayer membrane model.

Supramolecular interactions are well recognized and many of them have been extensively studied in chemistry. The formation of supramolecular complexes that rely on weak force interactions are less well studied in bilayer membranes. Herein, a supported bilayer membrane is used to probe the penetration of a complex between tetracycline and a macrocyclic polyether. In a number of bacterial systems, the presence of the macrocycle has been found to significantly enhance the potency of the antimicrobial in vitro. The crown·tetracycline complex has been characterized in solution, neutron reflectometry has probed complex penetration, and the phenomena have been modeled by computational methods.

Deep neural network based quantum simulations and quasichemical theory for accurate modeling of molten salt thermodynamics.

With dual goals of efficient and accurate modeling of solvation thermodynamics in molten salt liquids, we employ ab initio molecular dynamics (AIMD) simulations, deep neural network interatomic potentials (NNIP), and quasichemical theory (QCT) to calculate the excess chemical potentials for the solute ions Na+ and Cl- in the molten NaCl liquid. NNIP-based molecular dynamics simulations accelerate the calculations by 3 orders of magnitude and reduce the uncertainty to 1 kcal mol-1. Using the Density Functional Theory (DFT) level of theory, the predicted excess chemical potential for the solute ion pair is -178.5 ± 1.1 kcal mol-1. A quantum correction of 13.7 ± 1.9 kcal mol-1 is estimated via higher-level quantum chemistry calculations, leading to a final predicted ion pair excess chemical potential of -164.8 ± 2.2 kcal mol-1. The result is in good agreement with a value of -163.5 kcal mol-1 obtained from thermo-chemical tables. This study validates the application of QCT and NNIP simulations to the molten salt liquids, allowing for significant insights into the solvation thermodynamics crucial for numerous molten salt applications.

Specific Ion Solvation and Pairing Effects in Glycerol Carbonate.

Identifying the driving forces behind the solvation of inorganic salts by nonaqueous solvents is an important step in the development of green solvents. Here we focus on one promising solvent: glycerol carbonate (GC). Using ab initio molecular dynamics simulations, we build upon our previous work by detailing glycerol carbonate's interactions with a series of anions, a lithium ion, and the LiF ion pair. Through these investigations, we highlight the changes in solvation behavior as the anion size increases, the competition of binding shown by lithium for the oxygens of GC, and the behavior of the LiF ion pair in a GC solution. These results indicate the importance of the cation's identity in ion-pairing structure and dynamics and lend insight into the key factors behind the specific ion effects seen in GC.

Condensed Phase Water Molecular Multipole Moments from Deep Neural Network Models Trained on Ab Initio Simulation Data.

Ionic solvation phenomena in liquids involve intense interactions in the inner solvation shell. For interactions beyond the first shell, the ion-solvent interaction energies result from the sum of many smaller-magnitude contributions that can still include polarization effects. Deep neural network (DNN) methods have recently found wide application in developing efficient molecular models that maintain near-quantum accuracy. Here we extend the DeePMD-kit code to produce accurate molecular multipole moments in the bulk and near interfaces. The new method is validated by comparing the DNN moments with those generated by ab initio simulations. The moments are used to compute the electrostatic potential at the center of a molecular-sized hydrophobic cavity in water. The results show that the fields produced by the DNN models are in quantitative agreement with the AIMD-derived values. These efficient methods will open the door to more accurate solvation models for large solutes such as proteins.

Quantum Simulations of Hydrogen Bonding Effects in Glycerol Carbonate Electrolyte Solutions.

The need for environmentally friendly nonaqueous solvents in electrochemistry and other fields has motivated recent research into the molecular-level solvation structure, thermodynamics, and dynamics of candidate organic liquids. In this paper, we present the results of quantum density functional theory simulations of glycerol carbonate (GC), a molecule that has been proposed as a solvent for green industrial chemistry, nonaqueous alternatives for biocatalytic reactions, and liquid media in energy storage devices. We investigate the structure and dynamics of both the pure GC liquid and electrolyte solutions containing KF and KCl ion pairs. These simulations reveal the importance of hydrogen bonding that controls the structural and dynamic behavior of the pure liquid and ion association in the electrolyte solutions. The results illustrate the difficulties associated with classical modeling of complex organic solvents. The simulations lead to a better understanding of the underlying mechanisms behind the previously observed peculiar ion-specific behavior in GC electrolyte solutions.

Absolute ion hydration free energy scale and the surface potential of water via quantum simulation.

With a goal of determining an absolute free energy scale for ion hydration, quasi-chemical theory and ab initio quantum mechanical simulations are employed to obtain an accurate value for the bulk hydration free energy of the Na+ ion. The free energy is partitioned into three parts: 1) the inner-shell or chemical contribution that includes direct interactions of the ion with nearby waters, 2) the packing free energy that is the work to produce a cavity of size λ in water, and 3) the long-range contribution that involves all interactions outside the inner shell. The interfacial potential contribution to the free energy resides in the long-range term. By averaging cation and anion data for that contribution, cumulant terms of all odd orders in the electrostatic potential are removed. The computed total is then the bulk hydration free energy. Comparison with the experimentally derived real hydration free energy produces an effective surface potential of water in the range -0.4 to -0.5 V. The result is consistent with a variety of experiments concerning acid-base chemistry, ion distributions near hydrophobic interfaces, and electric fields near the surface of water droplets.

Investigating partitioning of free versus macrocycle bound guest into a model POPC lipid bilayer.

We report on the permeation of free and macrocycle-bound avobenzone across a POPC lipid bilayer through combined neutron reflectometry experiments and molecular dynamics simulations. Results indicate that the p-phosphonated calix[8]arene macrocycle limits the avobenzone penetration into the upper leaflet of the membrane. Hence, it could serve as a useful vehicle for safer formulations.

The Importance of the Water Molecular Quadrupole for Estimating Interfacial Potential Shifts Acting on Ions Near the Liquid-Vapor Interface.

Interfacial electrostatic potential gradients arise from nonuniform charge distributions encountered crossing the interface. The charges involved can include the molecular charges predominantly bound to each neutral solvent molecule and distributions of ions (or electrons) free to move in the interfacial region. This paper focuses on the solvent contribution to the interfacial potential. Quasichemical theory (QCT) provides a physical framework for the analysis of near-local (chemical) and far-field contributions to ion solvation free energies. Here, we utilize QCT to analyze cavity net potentials that contribute to the single-ion real solvation free energy. In particular, we discuss the results of molecular dynamics simulations of water droplets large enough to exhibit bulklike behavior in the droplet interior. A multipolar analysis of the cavity potential illustrates the importance of the solvent molecular quadrupole due to the near-cancellation of the dipolar contributions from the cavity-liquid and liquid-vapor interfaces. The results reveal the physical origin of the previously observed strong classical model dependence of the cavity potential.

Re-examining the tetraphenyl-arsonium/tetraphenyl-borate (TATB) hypothesis for single-ion solvation free energies.

Attempts to establish an absolute single-ion hydration free energy scale have followed multiple strategies. Two central themes consist of (1) employing bulk pair thermodynamic data and an underlying interfacial-potential-free model to partition the hydration free energy into individual contributions [Marcus, Latimer, and tetraphenyl-arsonium/tetraphenyl-borate (TATB) methods] or (2) utilizing bulk thermodynamic and cluster data to estimate the free energy to insert a proton into water, including in principle an interfacial potential contribution [the cluster pair approximation (CPA)]. While the results for the hydration free energy of the proton agree remarkably well between the three approaches in the first category, the value differs from the CPA result by roughly +10 kcal/mol, implying a value for the effective electrochemical surface potential of water of -0.4 V. This paper provides a computational re-analysis of the TATB method for single-ion free energies using quasichemical theory. A previous study indicated a significant discrepancy between the free energies of hydration for the TA cation and the TB anion. We show that the main contribution to this large computed difference is an electrostatic artifact arising from modeling interactions in periodic boundaries. No attempt is made here to develop more accurate models for the local ion/solvent interactions that may lead to further small free energy differences between the TA and TB ions, but the results clarify the primary importance of interfacial potential effects for analysis of the various free energy scales. Results are also presented, related to the TATB assumption in the organic solvents dimethyl sulfoxide and 1,2-dichloroethane.

Bowl-in-bowl complex formation with mixed sized calixarenes: adaptivity towards guest binding.

We demonstrated the organization of two differently sized calixarenes C-methylresorcin[4]arene (RsC1) and either calix[6]arene (Calix6) or calix[8]arene (Calix8), where the lower rim of RsC1 partially overlaps with the upper rim of Calix6 or Calix8. An adaptive nature of the heteromacrocyclic assembly towards the binding of a model guest has been observed.

Structure and polarization near the Li+ ion in ethylene and propylene carbonates.

Research on fundamental interactions in Li-ion batteries is accelerating due to the importance of developing batteries with enhanced energy and power densities while maintaining safety. Improving electrode materials and controlling the formation of the solid electrolyte interphase during the first battery charge have been the main focus areas for research. Ion-solvent interactions in the electrolyte are also of great importance in tuning solvation and transport properties, however. Here we present ab initio density functional theory simulations of a Li+ ion in ethylene and propylene carbonates. The aim is to obtain a detailed analysis of local solvation structure and solvent polarization near the ion and in the bulk. The results indicate the significance of molecular polarization for developing accurate solvation models. The simulations illustrate the substantial differences between ion solvation in water and in organic materials.

Free Energies of Ion Binding in the Bacterial CLC-ec1 Chloride Transporter with Implications for the Transport Mechanism and Selectivity.

The chloride channel/transporter family of proteins facilitates anion transport across biological membranes. There is extensive physiological and bioinformatic evidence that the channels and transporters are closely related. Each monomer of a homodimeric CLC transport protein contains a narrow selectivity filter. Investigating the ion binding properties inside the filter is crucial for understanding key mechanistic states during ion transit. Here computer simulations are used to explore the free energies of Cl(-) ions in the binding sites of the wild-type CLC-ec1 transporter and its mutant E148A. Specifically, a local molecular field theory approach for free energy calculations is exploited to compute the absolute free energies in water and in the protein binding sites. The calculations indicate a close synergy between anion binding and protonation of the external glutamate gate. Electrostatic differences between the bacterial CLC-ec1 and eukaryotic CmCLC transporters revealed by these and other simulations help to rationalize the observed differing structures in the pore region. In addition, quantum chemical calculations on the F(-), Cl(-), and Br(-) ions in the central binding site are used to examine ion selectivity. The calculations show a significant extent of charge transfer from the ion to the nearby residues. The computed free energies, in conjunction with experimental measurements, place constraints on proposed mechanisms for the transport cycle.

Models of Ion Solvation Thermodynamics in Ethylene Carbonate and Propylene Carbonate.

Ethylene carbonate (EC) and propylene carbonate (PC) are organic solvents used extensively in energy storage applications such as lithium-ion batteries and supercapacitors. Using statistical mechanical theory and computer simulations, this paper compares and contrasts the thermodynamics of ion solvation in EC and PC with the behavior observed in water. The EC and PC solvents are modeled with the AMBER (GAFF) force field. Ion-solvent interactions are treated with two point-charge models: one using an existing Lennard-Jones ion parameter set optimized for solvation in water, and the other based on high-level quantum calculations on ion-solvent dimers and fitting to a Buckingham-type potential form. The second model produces a coordination number for the Li(+) ion in closer agreement with experiment. Neither model yields consistently accurate solvation thermodynamic quantities (free energies, enthalpies, and entropies), however. The simulations and thermodynamic analysis illustrate key physical aspects of the solvation; the studies also point to necessary modifications of these simple models. In particular, the calculations show that polarization and associated dispersion forces are important and that well-optimized polarizable or quantum models are likely required to accurately reproduce condensed-phase properties of ions in these technologically important solvents.

A real-space stochastic density matrix approach for density functional electronic structure.

The recent development of real-space grid methods has led to more efficient, accurate, and adaptable approaches for large-scale electrostatics and density functional electronic structure modeling. With the incorporation of multiscale techniques, linear-scaling real-space solvers are possible for density functional problems if localized orbitals are used to represent the Kohn-Sham energy functional. These methods still suffer from high computational and storage overheads, however, due to extensive matrix operations related to the underlying wave function grid representation. In this paper, an alternative stochastic method is outlined that aims to solve directly for the one-electron density matrix in real space. In order to illustrate aspects of the method, model calculations are performed for simple one-dimensional problems that display some features of the more general problem, such as spatial nodes in the density matrix. This orbital-free approach may prove helpful considering a future involving increasingly parallel computing architectures. Its primary advantage is the near-locality of the random walks, allowing for simultaneous updates of the density matrix in different regions of space partitioned across the processors. In addition, it allows for testing and enforcement of the particle number and idempotency constraints through stabilization of a Feynman-Kac functional integral as opposed to the extensive matrix operations in traditional approaches.

The thermodynamics of proton hydration and the electrochemical surface potential of water.

The free energy change for transferring a single ion across the water liquid/vapor interface includes an electrochemical surface potential contribution. Since this potential is not directly accessible to thermodynamic measurement, several extra-thermodynamic approaches have been employed to infer its sign and magnitude, with a resulting wide spread of values. Here, we examine further the thermodynamics of proton hydration and the electrochemical surface potential of water along three directions: (1) a basic relation of interfacial electrostatics and experimental results on ion distributions near a water/organic interface are employed to infer a solvent contribution to the electrochemical surface potential, (2) a re-analysis is performed of the existing bulk and cluster ion hydration data, and (3) extensive computational modeling is conducted to examine the size dependence of hydration enthalpy differences for the NaF ion pair between the small cluster and the converged bulk limits. The computational studies include classical polarizable models and high-level quantum chemical methods. The new theoretical analysis of existing experimental data and the combined classical/quantum modeling lead to results consistent with our previously derived proton hydration quantities.