Philip Mason

Electrolyte-to-metal transitions in liquids represent a critical process in the evolution of excess electrons from localized species into a delocalized conduction band. Alkali metal--ammonia solutions are the textbook example, displaying a gradual progression from blue electrolytes to metallic gold liquids. In contrast, preparing the analogous aqueous solutions was long deemed impossible as alkali metals ignite or even explode on contact with water. Moreover, individual electrons solvated in water are more strongly bound than in liquid ammonia, which suggests that electrolyte-to-metal transitions may be inhibited, or only occur at very high alkali metal concentrations. Here we combine optical spectroscopy with ab initio molecular dynamics to show that aqueous alkali metal solutions can not only be prepared by adsorbing water vapor on alkali metal alloys of varying compositions but that they also undergo a dynamic, fluctuating electrolyte-to-metal transition. Simulations reveal femtosecond-scale flipping between electrolyte and metallic states, while experiments confirm the evolution of the metallic character via plasmonic signatures of distinct colors. Water can thus not only form a metallic solution but also exhibits a dynamic, rapidly fluctuating non-metal-to-metal transition.

Cation-π interactions involving the tetramethylammonium motif are prevalent in biological systems, playing crucial roles in membrane protein function, DNA expression regulation, and protein folding. However, accurately modeling cation-π interactions where electronic polarization plays a critical role is computationally challenging, especially in large biomolecular systems. This study implements a physically justified electronic continuum correction (ECC) to the CHARMM36 force field, scaling ionic charges by a factor of 0.75 to effectively account for electronic polarization without additional computational overhead. This approach, while not specifically designed for cation-π interactions, is shown here to significantly improve predictions of the structure of an aqueous tetramethylammonium-pyridine complex as compared to neutron diffraction data. This result, together with computational predictions for the structure of the aqueous tetramethylammonium-phenol complex, underscores the potential of ECC as a versatile method to improve the description of cation-π interactions in biomolecular simulations.

Charge scaling, also denoted as the electronic continuum correction, has proven to be an efficient method of effectively including electronic polarization in force field molecular dynamics simulations without additional computational costs. However, scaling charges in existing force fields, fitted at least in part to experimental data, leads to inconsistencies such as overscaling. We have, therefore, recently developed a 4-site water model consistent with charge scaling, i.e., possessing the correct low-frequency dielectric constant of 45. Here, we build on top of this water charge scaled models of biologically relevant Li+, Na+, K+, Ca2+, Mg2+ cations and Cl−, Br−, and I−, employing machine learning to streamline and speed-up the parameterization process. On the one hand, we show that the present model outperforms the best existing charge scaled model of aqueous ions. On the other hand, the present work points to a future need for improving consistently and simultaneously the water and ion models within the electronic continuum correction framework.

Cation–π interactions involving the tetramethylammonium motif are common in biological systems, where they play essential roles in membrane protein function, DNA expression regulation, and protein folding. However, accurately modeling cation–π interactions, where electronic polarization is crucial, presents a significant computational challenge, especially in large biomolecular systems. This study applies a physically justified electronic continuum correction (ECC) to the CHARMM36 force field, scaling ionic charges by a factor of 0.75 to effectively account for electronic polarization without adding computational overhead. While not specifically designed for cation–π interactions, this approach significantly improves predictions of the structure of an aqueous tetramethylammonium–pyridine complex compared to neutron diffraction data. These results, along with computational predictions for the structure of the aqueous tetramethylammonium–phenol complex, highlight the potential of ECC as a versatile method for improving the description of cation–π interactions in biomolecular simulations.

Ion pairing in TMA-acetate solutions is probed by combining neutron scattering with isotopic substitution (NDIS) with force field and ab initio molecular dynamics (MD) simulations.

Tetramethylammonium (TMA) is a ubiquitous cationic motif in biochemistry, found in the charged choline headgroup of membrane phospholipids and in tri-methylated lysine residues, which modulate histone-DNA interactions and impact epigenetic mechanisms. TMA interactions with anionic species, particularly carboxylate groups of amino acid residues and extracellular sugars, are of substantial biological relevance, as these interactions mediate a wide range of cellular processes. This study investigates the molecular interactions between TMA and acetate, representing carboxylate-containing groups, using neutron scattering experiments complemented by force field and ab initio molecular dynamics (MD) simulations. Neutron diffraction with isotopic substitution reveals specific ion pairing signatures between TMA and acetate, with simulations providing a detailed interpretation of the ion pairing structures. Force fields, notably CHARMM36 with the electronic continuum correction (ECC) (by a factor of 0.85) and AMBER99SB, capture essential pairing characteristics, but only revPBE-based ab initio MD simulations accurately model specific experimental features such as the low Q peak intensity in reciprocal space. Our study delivers a refined molecular model of TMA–carboxylate interactions, guiding the selection of force fields for complex biological systems where such interactions are of a significant importance.

ProsECCo75 is an optimized force field effectively incorporating electronic polarization via charge scaling. It aims to enhance the accuracy of nominally nonpolarizable molecular dynamics (MD) simulations for interactions in biologically relevant systems involving water, ions, proteins, lipids, and saccharides. Recognizing the inherent limitations of nonpolarizable force fields in precisely modeling electrostatic interactions essential for various biological processes, we mitigate these shortcomings by accounting for electronic polarizability in a physical rigorous mean-field way that does not add to computational costs. With this scaling of (both integer and partial) charges within the CHARMM36 framework, prosECCo75 addresses overbinding artifacts. This improves agreement with experimental ion binding data across a broad spectrum of systems - lipid membranes, proteins (including peptides and amino acids), and saccharides - without compromising their biomolecular structures. prosECCo75 thus emerges as a computationally efficient tool providing enhanced accuracy and broader applicability in simulating the complex interplay of interactions between ions and biomolecules, pivotal for improving our understanding of many biological processes.

Neutron scattering and molecular dynamics studies were performed on a concentrated aqueous tetramethylammonium (TMA) chloride solution to gain insight into the hydration shell structure of TMA, which is relevant for understanding its behavior in biological contexts of, e.g., properties of phospholipid membrane headgroups or interactions between DNA and histones. Specifically, neutron diffraction with isotopic substitution experiments were performed on TMA and water hydrogens to extract the specific correlation between hydrogens in TMA (H_TMA) and hydrogens in water (H_W). Classical molecular dynamics simulations were performed to help interpret the experimental neutron scattering data. Comparison of the hydration structure and simulated neutron signals obtained with various force field flavors (e.g. overall charge, charge distribution, polarity of the CH bonds and geometry) allowed us to gain insight into how sensitive the TMA hydration structure is to such changes and how much the neutron signal can capture them. We show that certain aspects of the hydration, such as the correlation of the hydrogen on TMA to hydrogen on water, showed little dependence on the force field. In contrast, other correlations, such as the ion–ion interactions, showed more marked changes. Strikingly, the neutron scattering signal cannot discriminate between different hydration patterns. Finally, ab initio molecular dynamics was used to examine the three-dimensional hydration structure and thus to benchmark force field simulations. Overall, while neutron scattering has been previously successfully used to improve force fields, in the particular case of TMA we show that it has only limited value to fully determine the hydration structure, with other techniques such as ab initio MD being of a significant help.

Neutron scattering and molecular dynamics studies were performed on a concentrated aqueous tetramethylammonium (TMA) chloride solution to gain insight into the hydration shell structure of TMA, which is relevant for understanding its behavior in biological contexts of, e.g., properties of phospholipid membrane headgroups or interactions between DNA and histones. Specifically, neutron diffraction with isotopic substitution experiments were performed on TMA and water hydrogens to extract the specific correlation between hydrogens in TMA ($\mathrm{H_{TMA}}$) and hydrogens in water ($\mathrm{H_{W}}$). Classical molecular dynamics simulations were performed to help interpret the experimental neutron scattering data. Comparison of the hydration structure and simulated neutron signals obtained with various force field flavors (e.g. overall charge, charge distribution, polarity of the CH bonds and geometry) allowed us to gain insight into how sensitive the TMA hydration structure is to such changes and how much the neutron signal can capture them. We show that certain aspects of the hydration, such as the correlation of the hydrogen on TMA to hydrogen on water, showed little dependence on the force field. In contrast, other correlations, such as the ion-ion interactions, showed more marked changes. Strikingly, the neutron scattering signal cannot discriminate between different hydration patterns. Finally, ab initio molecular dynamics was used to examine the three-dimensional hydration structure and thus to benchmark force field simulations. Overall, while neutron scattering has been previously successfully used to improve force fields, in the particular case of TMA we show that it has only limited value to fully determine the hydration structure, with other techniques such as ab initio MD being of a significant help.