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We model the autoionization of water by determining the free energy of hydration of the major intermediate species of water ions. We represent the smallest ions─the hydroxide ion OH - , the hydronium ion H 3 O + , and the Zundel ion H 5 O 2 + ─by bonded models and the more extended ionic structures by strong nonbonded interactions (e.g., the Eigen H 9 O 4 + = H 3 O + + 3(H 2 O) and the Stoyanov H 13 O 6 + = H 5 O 2 + + 4(H 2 O)). Our models are faithful to the precise QM energies and their components to within 1% or less. Using the calculated free energies and atomization energies, we compute the p K a of pure water from first principles as a consistency check and arrive at a value within 1.3 log units of the experimental one. From these calculations, we conclude that the hydronium ion, and its hydrated state, the Eigen cation, are the dominant species in the water autoionization process.

We incorporate nuclear quantum effects (NQE) in condensed matter simulations by introducing short-range neural network (NN) corrections to the ab initio fitted molecular force field ARROW. Force field NN corrections are fitted to average interaction energies and forces of molecular dimers, which are simulated using the Path Integral Molecular Dynamics (PIMD) technique with restrained centroid positions. The NN-corrected force field allows reproduction of the NQE for computed liquid water and methane properties such as density, radial distribution function (RDF), heat of evaporation (HVAP), and solvation free energy. Accounting for NQE through molecular force field corrections circumvents the need for explicit computationally expensive PIMD simulations in accurate calculations of the properties of chemical and biological systems. The accuracy and locality of pairwise NN NQE corrections indicate that this approach could be applicable to complex heterogeneous systems, such as proteins.

We present a formalism of a neural network encoding bonded interactions in molecules. This intramolecular encoding is consistent with the models of intermolecular interactions previously designed by this group. Variants of the encoding fed into a corresponding neural network may be used to economically improve the representation of torsional degrees of freedom in any force field. We test the accuracy of the reproduction of the ab initio potential energy surface on a set of conformations of two dipeptides, methyl-capped ALA and ASP, in several scenarios. The encoding, either alone or in conjunction with an analytical potential, improves agreement with ab initio energies that are on par with those of other neural network-based potentials. Using the encoding and neural nets in tandem with an analytical model places the agreements firmly within "chemical accuracy" of ±0.5 kcal/mol.

A key goal of molecular modeling is the accurate reproduction of the true quantum mechanical potential energy of arbitrary molecular ensembles with a tractable classical approximation. The challenges are that analytical expressions found in general purpose force fields struggle to faithfully represent the intermolecular quantum potential energy surface at close distances and in strong interaction regimes; that the more accurate neural network approximations do not capture crucial physics concepts, e.g., nonadditive inductive contributions and application of electric fields; and that the ultra-accurate narrowly targeted models have difficulty generalizing to the entire chemical space. We therefore designed a hybrid wide-coverage intermolecular interaction model consisting of an analytically polarizable force field combined with a short-range neural network correction for the total intermolecular interaction energy. Here, we describe the methodology and apply the model to accurately determine the properties of water, the free energy of solvation of neutral and charged molecules, and the binding free energy of ligands to proteins. The correction is subtyped for distinct chemical species to match the underlying force field, to segment and reduce the amount of quantum training data, and to increase accuracy and computational speed. For the systems considered, the hybrid ab initio parametrized Hamiltonian reproduces the two-body dimer quantum mechanics (QM) energies to within 0.03 kcal/mol and the nonadditive many-molecule contributions to within 2%. Simulations of molecular systems using this interaction model run at speeds of several nanoseconds per day.

Illness negatively affects all aspects of life and one major cause of illness is viral infections. Some viral infections can last for weeks; others, like influenza (the flu), can resolve quickly. During infections, uninfected cells can replicate in order to replenish the cells that have died due to the virus. Many viral models, especially those for short-lived infections like influenza, tend to ignore cellular regeneration since many think that uncomplicated influenza resolves much faster than cells regenerate. This research accounts for cellular regeneration, using an agent-based framework, and varies the regeneration rate in order to understand how cell regeneration affects viral infection dynamics under assumptions of different modes of transmission. We find that although the general trends in peak viral load, time of viral peak, and chronic viral load as regeneration rate changes are the same for cell-free or cell-to-cell transmission, the changes are more extreme for cell-to-cell transmission due to limited access of infected cells to newly generated cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Protein-ligand binding free-energy calculations using molecular dynamics (MD) simulations have emerged as a powerful tool for in silico drug design. Here, we present results obtained with the ARROW force field (FF)─a multipolar polarizable and physics-based model with all parameters fitted entirely to high-level ab initio quantum mechanical (QM) calculations. ARROW has already proven its ability to determine solvation free energy of arbitrary neutral compounds with unprecedented accuracy. The ARROW FF parameterization is now extended to include coverage of all amino acids including charged groups, allowing molecular simulations of a series of protein-ligand systems and prediction of their relative binding free energies. We ensure adequate sampling by applying a novel technique that is based on coupling the Hamiltonian Replica exchange (HREX) with a conformation reservoir generated via potential softening and nonequilibrium MD. ARROW provides predictions with near chemical accuracy (mean absolute error of ∼0.5 kcal/mol) for two of the three protein systems studied here (MCL1 and Thrombin). The third protein system (CDK2) reveals the difficulty in accurately describing dimer interaction energies involving polar and charged species. Overall, for all of the three protein systems studied here, ARROW FF predicts relative binding free energies of ligands with a similar accuracy level as leading nonpolarizable force fields.

Real-world sensory-processing applications require compact, low-latency, and low-power computing systems. Enabled by their in-memory event-driven computing abilities, hybrid memristive-Complementary Metal-Oxide Semiconductor neuromorphic architectures provide an ideal hardware substrate for such tasks. To demonstrate the full potential of such systems, we propose and experimentally demonstrate an end-to-end sensory processing solution for a real-world object localization application. Drawing inspiration from the barn owl's neuroanatomy, we developed a bio-inspired, event-driven object localization system that couples state-of-the-art piezoelectric micromachined ultrasound transducer sensors to a neuromorphic resistive memories-based computational map. We present measurement results from the fabricated system comprising resistive memories-based coincidence detectors, delay line circuits, and a full-custom ultrasound sensor. We use these experimental results to calibrate our system-level simulations. These simulations are then used to estimate the angular resolution and energy efficiency of the object localization model. The results reveal the potential of our approach, evaluated in orders of magnitude greater energy efficiency than a microcontroller performing the same task., (© 2022. The Author(s).)

The main goal of molecular simulation is to accurately predict experimental observables of molecular systems. Another long-standing goal is to devise models for arbitrary neutral organic molecules with little or no reliance on experimental data. While separately these goals have been met to various degrees, for an arbitrary system of molecules they have not been achieved simultaneously. For biophysical ensembles that exist at room temperature and pressure, and where the entropic contributions are on par with interaction strengths, it is the free energies that are both most important and most difficult to predict. We compute the free energies of solvation for a diverse set of neutral organic compounds using a polarizable force field fitted entirely to ab initio calculations. The mean absolute errors (MAE) of hydration, cyclohexane solvation, and corresponding partition coefficients are 0.2 kcal/mol, 0.3 kcal/mol and 0.22 log units, i.e. within chemical accuracy. The model (ARROW FF) is multipolar, polarizable, and its accompanying simulation stack includes nuclear quantum effects (NQE). The simulation tools' computational efficiency is on a par with current state-of-the-art packages. The construction of a wide-coverage molecular modelling toolset from first principles, together with its excellent predictive ability in the liquid phase is a major advance in biomolecular simulation., (© 2022. The Author(s).)

Introduction: Background: the ketogenic diet (CD) is an established, effective non-pharmacological treatment for refractory epilepsy in childhood. Aim: the objective of this study was to compare the efficacy, the presence of undesirable effects, and adherence between the classic ketogenic diet (DCC) and the modified Atkins diet (DAM). Materials and methods: a retrospective and comparative investigation was carried out to evaluate the medical records of all the patients who started treatment with a ketogenic diet by the same team between 2008 and 2018. In all, 57 patients were started on a DAM diet and 19 patients were given a DCC diet. Results: it was observed that both the Atkins and the classic diets were equally effective (approximately, 80 %; p = 0.252). Regarding adherence, there was a significantly higher percentage of adherence to the Atkins diet than to the classic diet (p = 0.018). Fewer adverse effects were observed with DAM than with DCC (p = 0.012). In all, 21 % of patients under DAM had unfavorable effects (12/57), while 52.63 % of patients on DCC had complications (10/19). Conclusion: a comparable effectiveness in terms of crisis control was found between DAM and DCC. However, DAM exhibits a much better adherence than DCC, and its undesirable effects are milder, less common. That is why, according to other works, it is likely that DAM should be first-choice for patients with refractory epilepsy in a large percentage of cases.

SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) causes a variety of responses in those who contract the virus, ranging from asymptomatic infections to acute respiratory failure and death. While there are likely multiple mechanisms triggering severe disease, one potential cause of severe disease is the size of the initial inoculum. For other respiratory diseases, larger initial doses lead to more severe outcomes. We investigate whether there is a similar link for SARS-CoV-2 infections using the combination of an agent-based model (ABM) and a partial differential equation model (PDM). We use the model to examine the viral time course for different sizes of initial inocula, generating dose-response curves for peak viral load, time of viral peak, viral growth rate, infection duration, and area under the viral titer curve. We find that large initial inocula lead to short infections, but with higher viral titer peaks; and that smaller initial inocula lower the viral titer peak, but make the infection last longer.

The control of quantum coupling between nano-objects is essential to quantum technologies. Confined nanostructures, such as cavities, resonators, or quantum dots, are designed to enhance interactions between electrons, photons, or phonons, giving rise to new properties, on which devices are developed. The nature and strength of these interactions are often measured indirectly on an assembly of dissimilar objects. Here, we adopt an innovative point of view by directly mapping the coupling of single nanostructures using scanning tunneling microscopy and spectroscopy (STM and STS). We take advantage of the unique capabilities of STM/STS to map simultaneously the nano-object's morphology and electronic density in order to observe in real space the electronic coupling of pairs of In(Ga)As/GaAs self-assembled quantum dots (QDs), forming quantum dot molecules (QDMs). Differential conductance maps d I/d V ( E, x, y) demonstrate the presence of an effective electronic coupling, leading to bonding and antibonding states, even for dissymmetric QDMs. The experimental results are supported by numerical simulations. The actual geometry of the QDMs is taken into account to determine the strength of the coupling, showing the crucial role of quantum dot size and pair separation for device growth optimization.

In many important processes in chemistry, physics, and biology the nuclear degrees of freedom cannot be described using the laws of classical mechanics. At the same time, the vast majority of molecular simulations that employ wide-coverage force fields treat atomic motion classically. In light of the increasing desire for and accelerated development of quantum mechanics (QM)-parameterized interaction models, we reexamine whether the classical treatment is sufficient for a simple but crucial chemical species: alkanes. We show that when using an interaction model or force field in excellent agreement with the "gold standard" QM data, even very basic simulated properties of liquid alkanes, such as densities and heats of vaporization, deviate significantly from experimental values. Inclusion of nuclear quantum effects via techniques that treat nuclear degrees of freedom using the laws of classical mechanics brings the simulated properties much closer to reality., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

We present the performance of blind predictions of water-cyclohexane distribution coefficients for 53 drug-like compounds in the SAMPL5 challenge by three methods currently in use within our group. Two of them utilize QMPFF3 and ARROW, polarizable force-fields of varying complexity, and the third uses the General Amber Force-Field (GAFF). The polarizable FF's are implemented in an in-house MD package, Arbalest. We find that when we had time to parametrize the functional groups with care (batch 0), the polarizable force-fields outperformed the non-polarizable one. Conversely, on the full set of 53 compounds, GAFF performed better than both QMPFF3 and ARROW. We also describe the torsion-restrain method we used to improve sampling of molecular conformational space and thus the overall accuracy of prediction. The SAMPL5 challenge highlighted several drawbacks of our force-fields, such as our significant systematic over-estimation of hydrophobic interactions, specifically for alkanes and aromatic rings.