Nutritional responsiveness affects novel neutrophil parameters and reduces in-hospital mortality and costs in elective cancer oesophagectomy - a single centre, prospective, observational study.

INTRODUCTION: Malnutrition in surgical patients remains a common issue affecting the perioperative period. Oesophageal cancer is a disease associated with one of the highest malnutrition rates. Assessment of patient nutritional status remains a challenge due to limited validated tools. Novel parameters to identify malnourished patients and the effectiveness of preoperative nutritional intervention might improve treatment results in the perioperative period. MATERIAL AND METHODS: This was a prospective, observational, single-centre study of patients scheduled for elective oesophagectomy. The primary aim of this study was to establish the correlation between neutrophil reactivity intensity (NEUT-RI) and neutrophil granularity intensity (NEUT-GI) and patients' nutritional status. We divided patients into nutritional responders (R group) and nutritional non-responders (NR group) defined as regaining at least 25% of the maximum preoperative body weight loss during the preoperative period. RESULTS: The R group had significantly shorter intensive care unit (ICU) stays: 5.5 (4-8) vs. 13 (7-31) days ( P = 0.01). It resulted in a lower cost of ICU stays in the R group: 4775.2 (3938.9-7640.7) vs. 12255.8 (7787.6-49108.7) euro in the NR group ( P = 0.01). Between the R group and the NR group, we observed statistically significant differences in both preoperative NEUT-RI (48.6 vs. 53.4, P = 0.03) and NEUT-GI (154.6 vs. 159.3, P = 0.02). Apart from the T grade, the only preoperative factor associated with reduced mortality was the nutritional responsiveness: 11.1% vs. 71.4% ( P = 0.008). CONCLUSIONS: Preoperative nutritional responsiveness affects neutrophil intensity indexes and reduces in-hospital mortality and costs associated with hospital stay. Further research is required to determine the correlation between novel neutrophil parameters and patients' nutritional status.

Tuning the work function of graphite nanoparticles via edge termination.

Graphite nanoparticles are important in energy materials applications such as lithium-ion batteries (LIBs), supercapacitors and as catalyst supports. Tuning the work function of the nanoparticles allows local control of lithiation behaviour in LIBs, and the potential of zero charge of electrocatalysts and supercapacitors. Using large scale density functional theory (DFT) calculations, we find that the surface termination of multilayer graphene nanoparticles can substantially modify the work function. Calculations in vacuum and in electrolyte show that manipulating the edge termination substantially modifies the potential not only around the edge, but also on the basal plane. Termination with hydrogen or oxygen completely reverses the potential distribution surrounding the basal plane and edges. The trends can be explained based on the work function differences of the edges dependent on termination, and that of the basal plane. Electronic equilibration between different surfaces at the nanoscale allows manipulation of the work function. We demonstrate a link between the area of the graphite basal plane via changing the nanoparticle size, and the work function. We expect that these insights can be utilised for local control of electrochemical functions of graphite nanoparticles prepared under oxidising or reducing conditions.

Massively parallel linear-scaling Hartree-Fock exchange and hybrid exchange-correlation functionals with plane wave basis set accuracy.

We extend our linear-scaling approach for the calculation of Hartree-Fock exchange energy using localized in situ optimized orbitals [Dziedzic et al., J. Chem. Phys. 139, 214103 (2013)] to leverage massive parallelism. Our approach has been implemented in the onetep (Order-N Electronic Total Energy Package) density functional theory framework, which employs a basis of non-orthogonal generalized Wannier functions (NGWFs) to achieve linear scaling with system size while retaining controllable near-complete-basis-set accuracy. For the calculation of Hartree-Fock exchange, we use a resolution-of-identity approach, where an auxiliary basis set of truncated spherical waves is used to fit products of NGWFs. The fact that the electrostatic potential of spherical waves (SWs) is known analytically, combined with the use of a distance-based cutoff for exchange interactions, leads to a calculation cost that scales linearly with the system size. Our new implementation, which we describe in detail, combines distributed memory parallelism (using the message passing interface) with shared memory parallelism (OpenMP threads) to efficiently utilize numbers of central processing unit cores comparable to, or exceeding, the number of atoms in the system. We show how the use of multiple time-memory trade-offs substantially increases performance, enabling our approach to achieve superlinear strong parallel scaling in many cases and excellent, although sublinear, parallel scaling otherwise. We demonstrate that in scenarios with low available memory, which preclude or limit the use of time-memory trade-offs, the performance degradation of our algorithm is graceful. We show that, crucially, linear scaling with system size is maintained in all cases. We demonstrate the practicability of our approach by performing a set of fully converged production calculations with a hybrid functional on large imogolite nanotubes up to over 1400 atoms. We finish with a brief study of how the employed approximations (exchange cutoff and the quality of the SW basis) affect the calculation walltime and the accuracy of the obtained results.

Electrochemistry from first-principles in the grand canonical ensemble.

Progress in electrochemical technologies, such as automotive batteries, supercapacitors, and fuel cells, depends greatly on developing improved charged interfaces between electrodes and electrolytes. The rational development of such interfaces can benefit from the atomistic understanding of the materials involved by first-principles quantum mechanical simulations with Density Functional Theory (DFT). However, such simulations are typically performed on the electrode surface in the absence of its electrolyte environment and at constant charge. We have developed a new hybrid computational method combining DFT and the Poisson-Boltzmann equation (P-BE) capable of simulating experimental electrochemistry under potential control in the presence of a solvent and an electrolyte. The charged electrode is represented quantum-mechanically via linear-scaling DFT, which can model nanoscale systems with thousands of atoms and is neutralized by a counter electrolyte charge via the solution of a modified P-BE. Our approach works with the total free energy of the combined multiscale system in a grand canonical ensemble of electrons subject to a constant electrochemical potential. It is calibrated with respect to the reduction potential of common reference electrodes, such as the standard hydrogen electrode and the Li metal electrode, which is used as a reference electrode in Li-ion batteries. Our new method can be used to predict electrochemical properties under constant potential, and we demonstrate this in exemplar simulations of the differential capacitance of few-layer graphene electrodes and the charging of a graphene electrode coupled to a Li metal electrode at different voltages.

Electronic structure calculations in electrolyte solutions: Methods for neutralization of extended charged interfaces.

Density functional theory (DFT) is often used for simulating extended materials such as infinite crystals or surfaces, under periodic boundary conditions (PBCs). In such calculations, when the simulation cell has non-zero charge, electrical neutrality has to be imposed, and this is often done via a uniform background charge of opposite sign ("jellium"). This artificial neutralization does not occur in reality, where a different mechanism is followed as in the example of a charged electrode in electrolyte solution, where the surrounding electrolyte screens the local charge at the interface. The neutralizing effect of the surrounding electrolyte can be incorporated within a hybrid quantum-continuum model based on a modified Poisson-Boltzmann equation, where the concentrations of electrolyte ions are modified to achieve electroneutrality. Among the infinite possible ways of modifying the electrolyte charge, we propose here a physically optimal solution, which minimizes the deviation of concentrations of electrolyte ions from those in open boundary conditions (OBCs). This principle of correspondence of PBCs with OBCs leads to the correct concentration profiles of electrolyte ions, and electroneutrality within the simulation cell and in the bulk electrolyte is maintained simultaneously, as observed in experiments. This approach, which we call the Neutralization by Electrolyte Concentration Shift (NECS), is implemented in our electrolyte model in the Order-N Electronic Total Energy Package (ONETEP) linear-scaling DFT code, which makes use of a bespoke highly parallel Poisson-Boltzmann solver, DL_MG. We further propose another neutralization scheme ("accessible jellium"), which is a simplification of NECS. We demonstrate and compare the different neutralization schemes on several examples.

The ONETEP linear-scaling density functional theory program.

We present an overview of the onetep program for linear-scaling density functional theory (DFT) calculations with large basis set (plane-wave) accuracy on parallel computers. The DFT energy is computed from the density matrix, which is constructed from spatially localized orbitals we call Non-orthogonal Generalized Wannier Functions (NGWFs), expressed in terms of periodic sinc (psinc) functions. During the calculation, both the density matrix and the NGWFs are optimized with localization constraints. By taking advantage of localization, onetep is able to perform calculations including thousands of atoms with computational effort, which scales linearly with the number or atoms. The code has a large and diverse range of capabilities, explored in this paper, including different boundary conditions, various exchange-correlation functionals (with and without exact exchange), finite electronic temperature methods for metallic systems, methods for strongly correlated systems, molecular dynamics, vibrational calculations, time-dependent DFT, electronic transport, core loss spectroscopy, implicit solvation, quantum mechanical (QM)/molecular mechanical and QM-in-QM embedding, density of states calculations, distributed multipole analysis, and methods for partitioning charges and interactions between fragments. Calculations with onetep provide unique insights into large and complex systems that require an accurate atomic-level description, ranging from biomolecular to chemical, to materials, and to physical problems, as we show with a small selection of illustrative examples. onetep has always aimed to be at the cutting edge of method and software developments, and it serves as a platform for developing new methods of electronic structure simulation. We therefore conclude by describing some of the challenges and directions for its future developments and applications.

The Role of Electrostatics in Enzymes: Do Biomolecular Force Fields Reflect Protein Electric Fields?

Preorganization of large, directionally oriented, electric fields inside protein active sites has been proposed as a crucial contributor to catalytic mechanism in many enzymes, and it may be efficiently investigated at the atomistic level with molecular dynamics simulations. Here, we evaluate the ability of the AMOEBA polarizable force field, as well as the additive Amber ff14SB and Charmm C36m models, to describe the electric fields present inside the active site of the peptidyl-prolyl isomerase cyclophilin A. We compare the molecular mechanical electric fields to those calculated with a fully first-principles quantum mechanical (QM) representation of the protein, solvent, and ions, and find that AMOEBA consistently shows far greater correlation with the QM electric fields than either of the additive force fields tested. Catalytically relevant fields calculated with AMOEBA were typically smaller than those observed with additive potentials, but were generally consistent with an electrostatically driven mechanism for catalysis. Our results highlight the accuracy and the potential advantages of using polarizable force fields in systems where accurate electrostatics may be crucial for providing mechanistic insights.

Mutually polarizable QM/MM model with in situ optimized localized basis functions.

We extend our recently developed quantum-mechanical/molecular mechanics (QM/MM) approach [Dziedzic et al., J. Chem. Phys. 145, 124106 (2016)] to enable in situ optimization of the localized orbitals. The quantum subsystem is described with onetep linear-scaling density functional theory and the classical subsystem - with the AMOEBA polarizable force field. The two subsystems interact via multipolar electrostatics and are fully mutually polarizable. A total energy minimization scheme is employed for the Hamiltonian of the coupled QM/MM system. We demonstrate that, compared to simpler models using fixed basis sets, the additional flexibility offered by in situ optimized basis functions improves the accuracy of the QM/MM interface, but also poses new challenges, making the QM subsystem more prone to overpolarization and unphysical charge transfer due to increased charge penetration. We show how these issues can be efficiently solved by replacing the classical repulsive van der Waals term for QM/MM interactions with an interaction of the electronic density with a fixed, repulsive MM potential that mimics Pauli repulsion, together with a modest increase in the damping of QM/MM polarization. We validate our method, with particular attention paid to the hydrogen bond, in tests on water-ion pairs, the water dimer, first solvation shells of neutral and charged species, and solute-solvent interaction energies. As a proof of principle, we determine suitable repulsive potential parameters for water, K+, and Cl-. The mechanisms we employed to counteract the unphysical overpolarization of the QM subsystem are demonstrated to be adequate, and our approach is robust. We find that the inclusion of explicit polarization in the MM part of QM/MM improves agreement with fully QM calculations. Our model permits the use of minimal size QM regions and, remarkably, yields good energetics across the well-balanced QM/MM interface.

DL_MG: A Parallel Multigrid Poisson and Poisson-Boltzmann Solver for Electronic Structure Calculations in Vacuum and Solution.

The solution of the Poisson equation is a crucial step in electronic structure calculations, yielding the electrostatic potential-a key component of the quantum mechanical Hamiltonian. In recent decades, theoretical advances and increases in computer performance have made it possible to simulate the electronic structure of extended systems in complex environments. This requires the solution of more complicated variants of the Poisson equation, featuring nonhomogeneous dielectric permittivities, ionic concentrations with nonlinear dependencies, and diverse boundary conditions. The analytic solutions generally used to solve the Poisson equation in vacuum (or with homogeneous permittivity) are not applicable in these circumstances, and numerical methods must be used. In this work, we present DL_MG, a flexible, scalable, and accurate solver library, developed specifically to tackle the challenges of solving the Poisson equation in modern large-scale electronic structure calculations on parallel computers. Our solver is based on the multigrid approach and uses an iterative high-order defect correction method to improve the accuracy of solutions. Using two chemically relevant model systems, we tested the accuracy and computational performance of DL_MG when solving the generalized Poisson and Poisson-Boltzmann equations, demonstrating excellent agreement with analytic solutions and efficient scaling to ∼109 unknowns and 100s of CPU cores. We also applied DL_MG in actual large-scale electronic structure calculations, using the ONETEP linear-scaling electronic structure package to study a 2615 atom protein-ligand complex with routinely available computational resources. In these calculations, the overall execution time with DL_MG was not significantly greater than the time required for calculations using a conventional FFT-based solver.

Electronically Excited States in Solution via a Smooth Dielectric Model Combined with Equation-of-Motion Coupled Cluster Theory.

We present a method for computing excitation energies for molecules in solvent, based on the combination of a minimal parameter implicit solvent model and the equation-of-motion coupled-cluster singles and doubles method (EOM-CCSD). In this method, the solvent medium is represented by a smoothly varying dielectric function, constructed directly from the quantum mechanical electronic density using only two tunable parameters. The solvent-solute electrostatic interactions are computed by numerical solution of the nonhomogeneous Poisson equation and incorporated at the Hartree-Fock stage of the EOM-CCSD calculation by modification of the electrostatic potential. We demonstrate the method by computing excited state transition energies and solvent shifts for several small molecules in water. Results are presented for solvated H2O, formaldehyde, acetone, and trans-acrolein, which have low-lying n → π* transitions and associated blue shifts in aqueous solution. Comparisons are made with experimental data and other theoretical approaches, including popular implicit solvation models and QM/MM methods. We find that our approach provides surprisingly good agreement with both experiment and the other models, despite its comparative simplicity. This approach only requires modification of the Fock operator and total energy expressions at the Hartree-Fock level-solvation effects enter into the EOM-CCSD calculation only through the Hartree-Fock orbitals. Our model provides a theoretically and computationally simple route for accurate simulations of excited state spectra of molecules in solution, paving the way for studies of larger and more complex molecules.

Performance of the AMOEBA Water Model in the Vicinity of QM Solutes: A Diagnosis Using Energy Decomposition Analysis.

The importance of incorporating solvent polarization effects into the modeling of solvation processes has been well-recognized, and therefore a new generation of hybrid quantum mechanics/molecular mechanics (QM/MM) approaches that accounts for this effect is desirable. We present a fully self-consistent, mutually polarizable QM/MM scheme using the AMOEBA force field, in which the total energy of the system is variationally minimized with respect to both the QM electronic density and the MM induced dipoles. This QM/AMOEBA model is implemented through the Q-Chem/LibEFP code interface and then applied to the evaluation of solute-solvent interaction energies for various systems ranging from the water dimer to neutral and ionic solutes (NH3, NH4+, CN-) surrounded by increasing numbers of water molecules (up to 100). In order to analyze the resulting interaction energies, we also utilize an energy decomposition analysis (EDA) scheme which identifies contributions from permanent electrostatics, polarization, and van der Waals (vdW) interaction for the interaction between the QM solute and the solvent molecules described by AMOEBA. This facilitates a component-wise comparison against full QM calculations where the corresponding energy components are obtained via a modified version of the absolutely localized molecular orbitals (ALMO)-EDA. The results show that the present QM/AMOEBA model can yield reasonable solute-solvent interaction energies for neutral and cationic species, while further scrutiny reveals that this accuracy highly relies on the delicate balance between insufficiently favorable permanent electrostatics and softened vdW interaction. For anionic solutes where the charge penetration effect becomes more pronounced, the QM/MM interface turns out to be unbalanced. These results are consistent with and further elucidate our findings in a previous study using a slightly different QM/AMOEBA model ( Dziedzic et al. J. Chem. Phys. 2016 , 145 , 124106 ). The implications of these results for further refinement of this model are also discussed.

Performance of extended Lagrangian schemes for molecular dynamics simulations with classical polarizable force fields and density functional theory.

Iterative energy minimization with the aim of achieving self-consistency is a common feature of Born-Oppenheimer molecular dynamics (BOMD) and classical molecular dynamics with polarizable force fields. In the former, the electronic degrees of freedom are optimized, while the latter often involves an iterative determination of induced point dipoles. The computational effort of the self-consistency procedure can be reduced by re-using converged solutions from previous time steps. However, this must be done carefully, as not to break time-reversal symmetry, which negatively impacts energy conservation. Self-consistent schemes based on the extended Lagrangian formalism, where the initial guesses for the optimized quantities are treated as auxiliary degrees of freedom, constitute one elegant solution. We report on the performance of two integration schemes with the same underlying extended Lagrangian structure, which we both employ in two radically distinct regimes-in classical molecular dynamics simulations with the AMOEBA polarizable force field and in BOMD simulations with the Onetep linear-scaling density functional theory (LS-DFT) approach. Both integration schemes are found to offer significant improvements over the standard (unpropagated) molecular dynamics formulation in both the classical and LS-DFT regimes.

Chemically Selective Alternatives to Photoferroelectrics for Polarization-Enhanced Photocatalysis: The Untapped Potential of Hybrid Inorganic Nanotubes.

Linear-scaling density functional theory simulation of methylated imogolite nanotubes (NTs) elucidates the interplay between wall-polarization, bands separation, charge-transfer excitation, and tunable electrostatics inside and outside the NT-cavity. The results suggest that integration of polarization-enhanced selective photocatalysis and chemical separation into one overall dipole-free material should be possible. Strategies are proposed to increase the NT polarization for maximally enhanced electron-hole separation.

TINKTEP: A fully self-consistent, mutually polarizable QM/MM approach based on the AMOEBA force field.

We present a novel quantum mechanical/molecular mechanics (QM/MM) approach in which a quantum subsystem is coupled to a classical subsystem described by the AMOEBA polarizable force field. Our approach permits mutual polarization between the QM and MM subsystems, effected through multipolar electrostatics. Self-consistency is achieved for both the QM and MM subsystems through a total energy minimization scheme. We provide an expression for the Hamiltonian of the coupled QM/MM system, which we minimize using gradient methods. The QM subsystem is described by the onetep linear-scaling DFT approach, which makes use of strictly localized orbitals expressed in a set of periodic sinc basis functions equivalent to plane waves. The MM subsystem is described by the multipolar, polarizable force field AMOEBA, as implemented in tinker. Distributed multipole analysis is used to obtain, on the fly, a classical representation of the QM subsystem in terms of atom-centered multipoles. This auxiliary representation is used for all polarization interactions between QM and MM, allowing us to treat them on the same footing as in AMOEBA. We validate our method in tests of solute-solvent interaction energies, for neutral and charged molecules, demonstrating the simultaneous optimization of the quantum and classical degrees of freedom. Encouragingly, we find that the inclusion of explicit polarization in the MM part of QM/MM improves the agreement with fully QM calculations.

Advanced Potential Energy Surfaces for Molecular Simulation.

Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms. We have now approached an era where multipole-based polarizable force fields can be routinely used to obtain computational results comparable to state-of-the-art density functional theory while reaching sampling statistics that are acceptable when compared to that obtained from simpler fixed partial charge force fields.

Anharmonic Infrared Spectroscopy through the Fourier Transform of Time Correlation Function Formalism in ONETEP.

Density functional theory molecular dynamics (DFT-MD) provides an efficient framework for accurately computing several types of spectra. The major benefit of DFT-MD approaches lies in the ability to naturally take into account the effects of temperature and anharmonicity, without having to introduce any ad hoc or a posteriori corrections. Consequently, computational spectroscopy based on DFT-MD approaches plays a pivotal role in the understanding and assignment of experimental peaks and bands at finite temperature, particularly in the case of floppy molecules. Linear-scaling DFT methods can be used to study large and complex systems, such as peptides, DNA strands, amorphous solids, and molecules in solution. Here, we present the implementation of DFT-MD IR spectroscopy in the ONETEP linear-scaling code. In addition, two methods for partitioning the dipole moment within the ONETEP framework are presented. Dipole moment partitioning allows us to compute spectra of molecules in solution, which fully include the effects of the solvent, while at the same time removing the solvent contribution from the spectra.

Density functional theory calculations on entire proteins for free energies of binding: application to a model polar binding site.

In drug optimization calculations, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method can be used to compute free energies of binding of ligands to proteins. The method involves the evaluation of the energy of configurations in an implicit solvent model. One source of errors is the force field used, which can potentially lead to large errors due to the restrictions in accuracy imposed by its empirical nature. To assess the effect of the force field on the calculation of binding energies, in this article we use large-scale density functional theory (DFT) calculations as an alternative method to evaluate the energies of the configurations in a "QM-PBSA" approach. Our DFT calculations are performed with a near-complete basis set and a minimal parameter implicit solvent model, within the self-consistent calculation, using the ONETEP program on protein-ligand complexes containing more than 2600 atoms. We apply this approach to the T4-lysozyme double mutant L99A/M102Q protein, which is a well-studied model of a polar binding site, using a set of eight small aromatic ligands. We observe that there is very good correlation between the MM and QM binding energies in vacuum but less so in the solvent. The relative binding free energies from DFT are more accurate than the ones from the MM calculations, and give markedly better agreement with experiment for six of the eight ligands. Furthermore, in contrast to MM-PBSA, QM-PBSA is able to correctly predict a nonbinder.

Electrostatic interactions in finite systems treated with periodic boundary conditions: application to linear-scaling density functional theory.

We present a comparison of methods for treating the electrostatic interactions of finite, isolated systems within periodic boundary conditions (PBCs), within density functional theory (DFT), with particular emphasis on linear-scaling (LS) DFT. Often, PBCs are not physically realistic but are an unavoidable consequence of the choice of basis set and the efficacy of using Fourier transforms to compute the Hartree potential. In such cases the effects of PBCs on the calculations need to be avoided, so that the results obtained represent the open rather than the periodic boundary. The very large systems encountered in LS-DFT make the demands of the supercell approximation for isolated systems more difficult to manage, and we show cases where the open boundary (infinite cell) result cannot be obtained from extrapolation of calculations from periodic cells of increasing size. We discuss, implement, and test three very different approaches for overcoming or circumventing the effects of PBCs: truncation of the Coulomb interaction combined with padding of the simulation cell, approaches based on the minimum image convention, and the explicit use of open boundary conditions (OBCs). We have implemented these approaches in the ONETEP LS-DFT program and applied them to a range of systems, including a polar nanorod and a protein. We compare their accuracy, complexity, and rate of convergence with simulation cell size. We demonstrate that corrective approaches within PBCs can achieve the OBC result more efficiently and accurately than pure OBC approaches.