Influence of Mg2+ Distribution on the Stability of Folded States of the Twister Ribozyme Revealed Using Grand Canonical Monte Carlo and Generative Deep Learning Enhanced Sampling.

Metal ions, particularly magnesium ions (Mg2+), play a role in stabilizing the tertiary structures of RNA molecules. Theoretical models and experimental techniques show that metal ions can change RNA dynamics and how it transitions through different stages of folding. However, the specific ways in which metal ions contribute to the formation and stabilization of RNA's tertiary structure are not fully understood at the atomic level. Here, we combined oscillating excess chemical potential Grand Canonical Monte Carlo (GCMC) and metadynamics to bias toward the sampling of unfolded states using reaction coordinates generated by machine learning allowing for examination of Mg2+-RNA interactions that contribute to stabilizing folded states of the pseudoknot found in the Twister ribozyme. GCMC is used to sample diverse ion distributions around the RNA with deep learning applied to iteratively generate system-specific reaction coordinates to maximize conformational sampling during metadynamics simulations. Results from 6 µs simulations performed on 9 individual systems indicate that Mg2+ ions play a crucial role in stabilizing the three-dimensional (3D) structure of the RNA by stabilizing specific interactions of phosphate groups or phosphate groups and bases of neighboring nucleotides. While many phosphates are accessible to interactions with Mg2+, it is observed that multiple, specific interactions are required to sample conformations close to the folded state; coordination of Mg2+ at individual specific sites facilitates sampling of folded conformations though unfolding ultimately occurs. It is only when multiple specific interactions occur, including the presence of specific inner-shell cation interactions linking two nucleotides, that conformations close to the folded state are stable. While many of the identified Mg2+ interactions are observed in the X-ray crystal structure of Twister, the present study suggests two new Mg2+ ion sites in the Twister ribozyme that contribute to stabilization. In addition, specific interactions with Mg2+ are observed that destabilize the local RNA structure, a process that may facilitate the folding of RNA into its correct structure.

Accurate modeling of RNA hairpins through the explicit treatment of electronic polarizability with the classical Drude oscillator force field.

Molecular dynamics (MD) simulations play a crucial role in modeling biomolecular systems in which the electrostatic interactions are critical in dictating the structural and dynamical properties. Thus, the treatment of the electrostatic interactions defined in the underlying force field (FF) strongly affects the simulation accuracy. Most FFs use fixed partial atomic charges to include electrostatic interactions, and therefore lack the electronic polarization response, representing an intrinsic limitation. To address this limitation, polarizable FFs have been developed that treat atomic polarizabilities explicitly. Here we present the application of the all-atom polarizable (Drude) and non-polarizable (CHARMM) nucleic acid FFs in RNA hairpin systems to investigate the impact of polarization on structural properties, dipole moment distributions, and cation interactions. Results show that the presence of polarizability in the FF significantly improves the stabilization of RNA hairpin structure. As expected, the distributions of dipole moments show more fluctuations when simulated using the polarizable FF, with the variation in dipoles contributing to the stabilization of the structures of the loop regions of the RNAs. Contact map analyses between the bases and cations show that the variation of the ion distribution around the entire hairpin is larger for the polarizable FF and the cations occupy the outer hydration shell to a greater extent. The presented results indicate the importance of the explicit treatment of electronic polarizability in molecular simulations of RNA, including in non-canonical regions.

Harnessing Deep Learning for Optimization of Lennard-Jones Parameters for the Polarizable Classical Drude Oscillator Force Field.

The outcomes of computational chemistry and biology research, including drug design, are significantly influenced by the underlying force field (FF) used in molecular simulations. While improved FF accuracy may be achieved via inclusion of explicit treatment of electronic polarization, such an extension must be accompanied by optimization of van der Waals (vdW) interactions, in the context of the Lennard-Jones (LJ) formalism in the present study. This is particularly challenging due to the extensive nature of chemical space combined with the correlated nature of LJ parameters. To address this challenge, a deep learning (DL)-based parametrization framework is developed, allowing for sampling of wide ranges of LJ parameters targeting experimental condensed phase thermodynamic properties. The present work utilizes this framework to develop the LJ parameters for atoms associated with four distinct groups covering 10 different atom types. Final parameter selection was facilitated by quantum mechanical data on rare-gas interactions with the training set molecules. The chosen parameters were then validated through experimental hydration free energies and condensed phase thermodynamic properties of validation set molecules to confirm transferability. The ultimate outcome of utilizing this framework is a set of LJ parameters in the context of the polarizable Drude FF, which demonstrated improvement in the reproduction of both experimental pure solvent and crystal properties and hydration free energies of the molecules compared to the additive CHARMM General FF (CGenFF) including the ability of the Drude FF to accurately reproduce both experimental pure solvent properties and hydration free energies. The study also shows how correlations between difference in the reproduction of condensed phase data between model compounds may be used to direct the selection of new atom types and training set molecules during FF development.

Atomistic level aqueous dissolution dynamics of NASICON-Type Li1+xAlxTi2-x(PO4)3 (LATP).

Advancing the atomistic level understanding of aqueous dissolution of multicomponent materials is essential. We combined ReaxFF and experiments to investigate the dissolution at the Li1+xAlxTi2-x(PO4)3-water interface. We demonstrate that surface dissolution is a sequentially dynamic process. The phosphate dissolution destabilizes the NASICON structure, which triggers a titanium-rich secondary phase formation.

Dynamics of the Chemically Driven Densification of Barium Titanate Using Molten Hydroxides.

Molten hydroxides, often used for crystal growth and nanoparticle synthesis, have recently been applied for the single step densification of several inorganic materials under moderate uniaxial pressures and 1000 °C below their usual sintering temperatures. The latter approach, termed cold sintering process (CSP), is a mechanochemically driven process that enables the densification of inorganic materials through a dissolution-precipitation creep mechanism. In this study, we report the main densification mechanisms of BaTiO3 in a NaOH-KOH eutectic mixture. A chemical insight at the atomistic level, investigated by ReaxFF molecular dynamics simulations, offers plausible ionic complex formation scenarios and reactions at the BaTiO3/molten hydroxide interface, enabling the dissolution-precipitation reactions and the subsequent cold sintering of BaTiO3.

Water-Mediated Surface Diffusion Mechanism Enables the Cold Sintering Process: A Combined Computational and Experimental Study.

The cold sintering process (CSP) densifies ceramics at much lower temperatures than conventional sintering processes. Several ceramics and composite systems have been successfully densified under cold sintering. For the grain growth kinetics of zinc oxide, reduced activation energies are shown, and yet the mechanism behind this growth is unknown. Herein, we investigate these mechanisms in more detail with experiments and ReaxFF molecular dynamics simulations. We investigated the recrystallization of zinc cations under various acidic conditions and found that their adsorption to the surface can be a rate-limiting factor for cold sintering. Our studies show that surface hydroxylation in CSP does not inhibit crystallization; in contrast, by creating a surface complex, it creates an orders of magnitude acceleration in surface diffusion, and in turn, accelerates recrystallization.

ReaxFF Molecular Dynamics Study on the Influence of Temperature on Adsorption, Desorption, and Decomposition at the Acetic Acid/Water/ZnO(101Ì 0) Interface Enabling Cold Sintering.

The reaction dynamics of a liquid-solid interface with the example of an acetic acid/water solution interacting with a ZnO(101̅0) surface was investigated using ReaxFF reactive force field-based molecular dynamics. The interactions were studied over a broad temperature range to assess the kinetics and reaction pathways. Two different acetic acid dissociation mechanisms are observed in the simulations: (1) deprotonation to surface cation, which produces a terminal hydroxyl and (2) deprotonation to a bridging hydroxyl, which results in water production. An increase in temperature promotes the dissociation of acetic acids and its adsorption to surface at first, but as the temperature increase continues, the surface coverage by acetates decreases due to evaporation from the surface or decomposition. The acetate decomposition starts with a nucleophilic attack of oxygen to methyl carbon and results in the production of carbon dioxide, which is consistent with experimental findings in the literature. The coverage of the surface by water molecules decreases as the system is heated up, which is also observed in other molecular dynamics studies. At elevated temperatures, acetate molecules are more stable than water molecules or bridging hydroxyls on the surface. These simulations validate the ReaxFF method for the water/organic mixture and metal oxide surface interactions and provide insights into structure and reactivity of aqueous solvents on metal oxide surfaces at elevated temperatures. Adsorption trends that are observed in this study are consistent with phenomenological Langmuir models. The reaction of acetic acid decomposition to smaller molecules such as CO2 and CH2O agrees with experimental observations. Understanding the details of these dynamic surface reactions are critical to understand important new cold sintering processes that utilize transient liquid and solid reactions, and the latter could be used to predict solvent selection for cold sintering.

Development of a ReaxFF reactive force field for lithium ion conducting solid electrolyte Li1+xAlxTi2-x(PO4)3 (LATP).

We developed a ReaxFF reactive force field for NASICON-type Li1+xAlxTi2-x(PO4)3 (LATP) materials, which is a promising solid-electrolyte that may enable all-solid-state lithium-ion batteries. The force field parameters were optimized based on density functional theory (DFT) data, including equations of state and the heats of formation of ternary metal oxides and metal phosphate crystal phases (e.g., LixTiO2, Al2TiO5, LiAlO2, AlPO4, Li3PO4 and LiTi2(PO4)3 (LTP)), and the energy barriers for Li diffusion in TiO2 and LTP via vacancies and interstitial sites. Using ReaxFF, the structural and the energetic features of LATP were described properly across various compositions - Li occupies more preferentially the interstitial site next to Al than next to Ti. Also, as observed in experimental data, the lattice parameters decrease when Ti is partly substituted by Al because of the smaller size of the Al cation. Using this force field, the diffusion mechanism and the ionic conductivity of Li in LTP and LATP were investigated at T = 300-1100 K. Low ionic conductivity (5.9 × 10-5 S cm-1 at 300 K) was obtained in LTP as previously reported. In LATP at x = 0.2, the ionic conductivity was slightly improved (8.4 × 10-5 S cm-1), but it is still below the experimental value, which is on the order of 10-4 to 10-3 S cm-1 at x = 0.3-0.5. At higher x (higher Al composition), LATP has a configurational diversity due to the Al substitution and the concomitant insertion of Li. By performing a hybrid MC/MD simulation for LATP at x = 0.5, a thermodynamically stable LATP configuration was obtained. The ionic conductivity of this LATP configuration was calculated to be 7.4 × 10-4 S cm-1 at 300 K, which is one order of magnitude higher than the ionic conductivity for LTP and LATP at x = 0.2. This value is in good agreement with our experimental value (2.5 × 10-4 S cm-1 at 300 K) and the literature values. The composition-dependent ionic conductivity of LATP was successfully demonstrated using the ReaxFF reactive force field, verifying the applicability of the LATP force field for the understanding of Li diffusion and the design of highly Li ion conductive solid electrolytes. Furthermore, our results also demonstrate the feasibility of the MC/MD method in modeling LATP configuration, and provide compelling evidence for the solid solution sensitivity on ionic conductivity.

ReaxFF molecular dynamics simulation of intermolecular structure formation in acetic acid-water mixtures at elevated temperatures and pressures.

The intermolecular structure formation in liquid and supercritical acetic acid-water mixtures was investigated using ReaxFF-based molecular dynamics simulations. The microscopic structures of acetic acid-water mixtures with different acetic acid mole fractions (1.0 ≥ xHAc ≥ 0.2) at ambient and critical conditions were examined. The potential energy surface associated with the dissociation of acetic acid molecules was calculated using a metadynamics procedure to optimize the dissociation energy of ReaxFF potential. At ambient conditions, depending on the acetic acid concentration, either acetic acid clusters or water clusters are dominant in the liquid mixture. When acetic acid is dominant (0.4 ≤ xHAc), cyclic dimers and chain structures between acetic acid molecules are present in the mixture. Both structures disappear at increased water content of the mixture. It was found by simulations that the acetic acid molecules released from these dimer and chain structures tend to stay in a dipole-dipole interaction. These structural changes are in agreement with the experimental results. When switched to critical conditions, the long-range interactions (e.g., second or fourth neighbor) disappear and the water-water and acetic acid-acetic acid structural formations become disordered. The simulated radial distribution function for water-water interactions is in agreement with experimental and computational studies. The first neighbor interactions between acetic acid and water molecules are preserved at relatively lower temperatures of the critical region. As higher temperatures are reached in the critical region, these interactions were observed to weaken. These simulations indicate that ReaxFF molecular dynamics simulations are an appropriate tool for studying supercritical water/organic acid mixtures.