Polysulfides in Magnesium-Sulfur Batteries.

Mg-S batteries hold great promise as a potential alternative to Li-based technologies. Their further development hinges on solving a few key challenges, including the lower capacity and poorer cycling performance when compared to Li counterparts. At the heart of the issues is the lack of knowledge on polysulfide chemical behaviors in the Mg-S battery environment. In this Review, a comprehensive overview of the current understanding of polysulfide behaviors in Mg-S batteries is provided. First, a systematic summary of experimental and computational techniques for polysulfide characterization is provided. Next, conversion pathways for Mg polysulfide species within the battery environment are discussed, highlighting the important role of polysulfide solubility in determining reaction kinetics and overall battery performance. The focus then shifts to the negative effects of polysulfide shuttling on Mg-S batteries. The authors outline various strategies for achieving an optimal balance between polysulfide solubility and shuttling, including the use of electrolyte additives, polysulfide-trapping materials, and dual-functional catalysts. Based on the current understanding, the directions for further advancing knowledge of Mg polysulfide chemistry are identified, emphasizing the integration of experiment with computation as a powerful approach to accelerate the development of Mg-S battery technology.

Heparan sulfate glycomimetics via iterative assembly of "clickable" disaccharides.

Heparan sulfate (HS) glycosaminoglycans are widely expressed on the mammalian cell surfaces and extracellular matrices and play important roles in a variety of cell functions. Studies on the structure-activity relationships of HS have long been hampered by the challenges in obtaining chemically defined HS structures with unique sulfation patterns. Here, we report a new approach to HS glycomimetics based on iterative assembly of clickable disaccharide building blocks that mimic the disaccharide repeating units of native HS. Variably sulfated clickable disaccharides were facilely assembled into a library of mass spec-sequenceable HS-mimetic oligomers with defined sulfation patterns by solution-phase iterative syntheses. Microarray and surface plasmon resonance (SPR) binding assays corroborated molecular dynamics (MD) simulations and confirmed that these HS-mimetic oligomers bind protein fibroblast growth factor 2 (FGF2) in a sulfation-dependent manner consistent with that of the native HS. This work established a general approach to HS glycomimetics that can potentially serve as alternatives to native HS in both fundamental research and disease models.

Characterizing Grain Boundary Effects on Mg2+ Conduction in Metal-Organic Frameworks.

Next-generation materials for fast ion conduction have the potential to revolutionize battery technology. Metal-organic frameworks (MOFs) are promising candidates for achieving this goal. Given their structural diversity, the design of efficient MOF-based conductors can be accelerated by a detailed understanding and accurate prediction of ion conductivity. However, the polycrystalline nature of solid-state materials requires consideration of grain boundary effects, which is complicated by challenges in characterizing grain boundary structures and simulating ensemble transport processes. To address this, we have developed an approach for modeling ion transport at grain boundaries and predicting their contribution to conductivity. Mg2+ conduction in the Mg-MOF-74 thin film was studied as a representative system. Using computational techniques and guided by experiments, we investigated the structural details of MOF grain boundary interfaces to determine accessible Mg2+ transport pathways. Computed transport kinetics were input into a simplified MOF nanocrystal model, which combines ion transport in the bulk structure and at grain boundaries. The model predicts Mg2+ conductivity in the MOF-74 film within chemical accuracy (<1 kcal/mol activation energy difference), validating our approach. Physically, Mg2+ conduction in MOF-74 is inhibited by strong Mg2+ binding at grain boundaries, such that only a small fraction of grain boundary alignments allow for fast Mg2+ transport. This results in a 2-3 order-of-magnitude reduction in conductivity, illustrating the critical impact of the grain boundary contribution. Overall, our work provides a computation-aided platform for molecular-level understanding of grain boundary effects and quantitative prediction of ion conductivity. Combined with experimental measurements, it can serve as a synergistic tool for characterizing the grain boundary composition of MOF-based conductors.

Precise Steric Features Control Aminoacyl-tRNA Accommodation on the Ribosome.

Protein synthesis involves a complex series of large-scale conformational changes in the ribosome. While long-lived intermediate states of these processes can be characterized by experiments, computational methods can be used to identify the interactions that contribute to the rate-limiting free-energy barriers. To this end, we use a simplified energetic model to perform molecular dynamics (MD) simulations of aminoacyl-tRNA (aa-tRNA) accommodation on the ribosome. While numerous studies have probed the energetics of the early stages of accommodation, we focus on the final stage of accommodation, where the 3'-CCA tail of aa-tRNA enters the peptidyl transferase center (PTC). These simulations show how a distinct intermediate is induced by steric confinement of the tail, immediately before it completes accommodation. Multiple pathways for 3'-CCA tail accommodation can be quantitatively distinguished, where the tail enters the PTC by moving past a pocket enclosed by Helix 89, 90, and 92, or through an alternate route formed by Helix 93 and the P-site tRNA. C2573, located within Helix 90, is shown to provide the largest contribution to this late-accommodation steric barrier, such that sub-Å perturbations to this residue can alter the time scale of tail accommodation by nearly an order of magnitude. In terms of biological function, these calculations suggest how this late-stage sterically induced barrier may contribute to tRNA proofreading by the ribosome.

Diffuse Ions Coordinate Dynamics in a Ribonucleoprotein Assembly.

Proper ionic concentrations are required for the functional dynamics of RNA and ribonucleoprotein (RNP) assemblies. While experimental and computational techniques have provided many insights into the properties of chelated ions, less is known about the energetic contributions of diffuse ions to large-scale conformational rearrangements. To address this, we present a model that is designed to quantify the influence of diffuse monovalent and divalent ions on the dynamics of biomolecular assemblies. This model employs all-atom (non-H) resolution and explicit ions, where effective potentials account for hydration effects. We first show that the model accurately predicts the number of excess Mg2+ ions for prototypical RNA systems, at a level comparable to modern coarse-grained models. We then apply the model to a complete ribosome and show how the balance between diffuse Mg2+ and K+ ions can control the dynamics of tRNA molecules during translation. The model predicts differential effects of diffuse ions on the free-energy barrier associated with tRNA entry and the energy of tRNA binding to the ribosome. Together, this analysis reveals the direct impact of diffuse ions on the dynamics of an RNP assembly.

SMOG 2 and OpenSMOG: Extending the limits of structure-based models.

Applying simulations with structure-based Go¯-like models has proven to be an effective strategy for investigating the factors that control biomolecular dynamics. The common element of these models is that some (or all) of the intra/inter-molecular interactions are explicitly defined to stabilize an experimentally determined structure. To facilitate the development and application of this broad class of models, we previously released the SMOG 2 software package. This suite allows one to easily customize and distribute structure-based (i.e., SMOG) models for any type of polymer-ligand system. The force fields generated by SMOG 2 may then be used to perform simulations in highly optimized MD packages, such as Gromacs, NAMD, LAMMPS, and OpenMM. Here, we describe extensions to the software and demonstrate the capabilities of the most recent version (SMOG v2.4.2). Changes include new tools that aid user-defined customization of force fields, as well as an interface with the OpenMM simulation libraries (OpenSMOG v1.1.0). The OpenSMOG module allows for arbitrary user-defined contact potentials and non-bonded potentials to be employed in SMOG models, without source-code modifications. To illustrate the utility of these advances, we present applications to systems with millions of atoms, long polymers and explicit ions, as well as models that include non-structure-based (e.g., AMBER-based) energetic terms. Examples include large-scale rearrangements of the SARS-CoV-2 Spike protein, the HIV-1 capsid with explicit ions, and crystallographic lattices of ribosomes and proteins. In summary, SMOG 2 and OpenSMOG provide robust support for researchers who seek to develop and apply structure-based models to large and/or intricate biomolecular systems.

Molecular-Level Insights into Selective Transport of Mg2+ in Metal-Organic Frameworks.

Metal-organic frameworks (MOF) are promising media for achieving solid-state Mg2+ conduction and developing a magnesium-based battery. To this end, the chemical behavior and transport properties of an Mg(TFSI)2/DME electrolyte system inside Mg-MOF-74 were studied by density functional theory (DFT). We found that inside the MOF chemical environment, solvent and anion molecules occupy the coordinatively unsaturated open metal sites of Mg-MOF-74, while Mg2+ ions adsorb directly onto the carboxylate group of the MOF organic linker. These predicted binding geometries were further corroborated by IR spectroscopy. We computed the free energies of desolvation of Mg2+ ions inside MOF to investigate the capacity of Mg-MOF-74 thin film to act as a separator for selective Mg2+ transport. We showed that Mg-MOF-74 could facilitate partial, but not full, desolvation of Mg2+. We found that the dominant minimum-energy pathway (MEP) for Mg2+ conduction inside Mg-MOF-74 corresponds to a "solvent hopping" mechanism, with an energy barrier of 4.4 kcal/mol. The molar conductivity of Mg2+ associated with the idealized solvent hopping mechanism along the MOF one-dimensional channel was predicted to be 2.4 × 10-3 S cm-1 M-1, which is one to two orders of magnitude greater than the experimentally measured value of 1.2 × 10-4 S cm-1 M-1 (with an estimated Mg2+ concentration). We have discussed several possible factors contributing to this apparent discrepancy. The current work demonstrates the validity of the computational strategies applied and the structural models constructed for the understanding of fast and selective Mg2+ transport in Mg-MOF-74, which serves as a cornerstone for studying transport of multivalent ions in MOFs. Furthermore, it provides detailed molecular-level insights that are not yet accessible experimentally.

A steric gate controls P/E hybrid-state formation of tRNA on the ribosome.

The ribosome is a biomolecular machine that undergoes multiple large-scale structural rearrangements during protein elongation. Here, we focus on a conformational rearrangement during translocation, known as P/E hybrid-state formation. Using a model that explicitly represents all non-hydrogen atoms, we simulated more than 120 spontaneous transitions, where the tRNA molecule is displaced between the P and E sites of the large subunit. In addition to predicting a free-energy landscape that is consistent with previous experimental observations, the simulations reveal how a six-residue gate-like region can limit P/E formation, where sub-angstrom structural perturbations lead to an order-of-magnitude change in kinetics. Thus, this precisely defined set of residues represents a novel target that may be used to control functional dynamics in bacterial ribosomes. This theoretical analysis establishes a direct relationship between ribosome structure and large-scale dynamics, and it suggests how next-generation experiments may precisely dissect the energetics of hybrid formation on the ribosome.

A Metal-Organic Framework Thin Film for Selective Mg2+ Transport.

The incompatibility between the anode and the cathode chemistry limits the used of Mg as an anode. This issue may be addressed by separating the anolyte and the catholyte with a membrane that only allows for Mg2+ transport. Mg-MOF-74 thin films were used as the separator for this purpose. It was shown to meet the needs of low-resistance, selective Mg2+ transport. The uniform MOF thin films supported on Au substrate with thicknesses down to ca. 202 nm showed an intrinsic resistance as low as 6.4â€…Ω cm2 , with the normalized room-temperature ionic conductivity of ca. 3.17×10-6  S cm-1 . When synthesized directly onto a porous anodized aluminum oxide (AAO) support, the resulting films were used as a standalone membrane to permit stable, low-overpotential Mg striping and plating for over 100 cycles at a current density of 0.05 mA cm-2 . The film was effective in blocking solvent molecules and counterions from crossing over for extended period of time.

Fluctuation Effects in the Adam-Gibbs Model of Cooperative Relaxation.

A generalization of the Adam-Gibbs model of relaxation in glass-forming liquids is formulated that takes into account fluctuation in the number of molecules inside the cooperative region. The configurational fraction links the excess entropy with kinetic properties described in the Adam-Gibbs model. We express the configurational fraction at the glass-transition temperature in terms of the width of the distribution of relaxation times, the nonlinearity parameter that demarcates the variations of the relaxation time with structure and temperature, the steepness index that is proportional to the slope of the logarithm of the relaxation time with respect to temperature, the excess heat capacity under constant pressure, and the number of correlated molecules or structural units. The configurational fraction in the absence of fluctuation effects is also determined for several glass-forming liquids at the glass-transition temperature.

Using SMOG 2 to Simulate Complex Biomolecular Assemblies.

Over the last 20 years, the application of structure-based (Go-like) models has ranged from protein folding with coarse-grained models to all-atom representations of large-scale molecular assemblies. While there are many variants that may be employed, the common feature of these models is that some (or all) of the stabilizing energetic interactions are defined based on the knowledge of a particular experimentally obtained conformation. With the generality of this approach, there was a need for a versatile computational platform for designing and implementing this class of models. To this end, the SMOG 2 software package provides an easy-to-use interface, where the user has full control of the model parameters. This software allows the user to edit XML-formatted files in order to provide definitions of new structure-based models. SMOG 2 reads these "template" files and maps the interactions onto specific structures, which are provided in PDB format. The force field files produced by SMOG 2 may then be used to perform simulations with a variety of popular molecular dynamics suites. In this chapter, we describe some of the key features of the SMOG 2 package, while providing examples and strategies for applying these techniques to complex (often large-scale) molecular assemblies, such as the ribosome.

RNA as a Complex Polymer with Coupled Dynamics of Ions and Water in the Outer Solvation Sphere.

We unravel the internal and collective modes of a widely studied 58-nucleotide rRNA fragment in solvent using atomically detailed molecular dynamics simulations. The variation of lifetimes for water hydrogen bonds with nucleotide groups indicates heterogeneity of water dynamics on the RNA surface. The time scales of interactions of the discrete water molecules with RNA nucleotides extend from several hundred picoseconds to a few nanoseconds. We determine all of the association sites and the spatial distribution of residence times for Mg2+, K+, and water molecules in those sites. We provide insights into the population of Mg2+ and K+ ions and water molecules in the outer sphere and how their fluctuations are intricately linked with the kinetics of the 58-mer. We find that many of the long-lived Mg2+ sites identified from the simulations agree with the locations of ions in the X-ray structure. We determine the excess ion atmosphere around the rRNA and compare it with experimental data. We investigate the collective behavior of RNA, ions, and water, by performing a joint principle component analysis for the Cartesian coordinates of the RNA phosphorus atoms and for the occupation counts of the association sites. Our results indicate that the 58-mer system is a complex polymer, composed of RNA that is encased by a fluctuating network of associated counterions, co-ions, and water.

Generalized Manning Condensation Model Captures the RNA Ion Atmosphere.

RNA is highly sensitive to the ionic environment and typically requires Mg(2+) to form compact structures. There is a need for models capable of describing the ion atmosphere surrounding RNA with quantitative accuracy. We present a model of RNA electrostatics and apply it within coarse-grained molecular dynamics simulation. The model treats Mg(2+) ions explicitly to account for ion-ion correlations neglected by mean-field theories. Since mean-field theories capture KCl well, it is treated implicitly by a generalized Manning counterion condensation model. The model extends Manning condensation to deal with arbitrary RNA conformations, nonlimiting KCl concentrations, and the ion inaccessible volume of RNA. The model is tested against experimental measurements of the excess Mg(2+) associated with the RNA, Γ(2+), because Γ(2+) is directly related to the Mg(2+)-RNA interaction free energy. The excellent agreement with experiment demonstrates that the model captures the ionic dependence of the RNA free energy landscape.

Reduced model captures Mg(2+)-RNA interaction free energy of riboswitches.

The stability of RNA tertiary structures depends heavily on Mg(2+). The Mg(2+)-RNA interaction free energy that stabilizes an RNA structure can be computed experimentally through fluorescence-based assays that measure Γ2+, the number of excess Mg(2+) associated with an RNA molecule. Previous explicit-solvent simulations predict that the majority of excess Mg(2+) ions interact closely and strongly with the RNA, unlike monovalent ions such as K(+), suggesting that an explicit treatment of Mg(2+) is important for capturing RNA dynamics. Here we present a reduced model that accurately reproduces the thermodynamics of Mg(2+)-RNA interactions. This model is able to characterize long-timescale RNA dynamics coupled to Mg(2+) through the explicit representation of Mg(2+) ions. KCl is described by Debye-Hückel screening and a Manning condensation parameter, which represents condensed K(+) and models its competition with condensed Mg(2+). The model contains one fitted parameter, the number of condensed K(+) ions in the absence of Mg(2+). Values of Γ2+ computed from molecular dynamics simulations using the model show excellent agreement with both experimental data on the adenine riboswitch and previous explicit-solvent simulations of the SAM-I riboswitch. This agreement confirms the thermodynamic accuracy of the model via the direct relation of Γ2+ to the Mg(2+)-RNA interaction free energy, and provides further support for the predictions from explicit-solvent calculations. This reduced model will be useful for future studies of the interplay between Mg(2+) and RNA dynamics.

Probing the origin of structural stability of single and double stapled p53 peptide analogs bound to MDM2.

The stabilization of secondary structure is believed to play an important role in the peptide-protein binding interaction. In this study, the α-helical conformation and structural stability of single and double stapled all-hydrocarbon cross-linked p53 peptides when bound and unbound to MDM2 are investigated. We determined the effects of the peptide sequence, the stereochemistry of the cross-linker, the conformation of the double bond in the alkene bridge, and the length of the bridge, to the relative stability of the α-helix structure. The binding affinity calculations by WaterMap provided over one hundred hydration sites in the MDM2 binding pocket where water density is greater than twice that of the bulk, and the relative value of free energy released by displacing these hydration sites. In agreement with the experimental data, potentials of mean force obtained by weighted histogram analysis methods indicated the order of peptides from lowest to highest binding affinity. Our study provides a comprehensive rationalization of the relationship between peptide stapling strategy, the secondary structural stability, and the binding affinity of p53/MDM2 complex. We hope our efforts can help to further the development of a new generation p53/MDM2 inhibitors that can reactivate the function of p53 as tumor suppressor gene.

Magnesium fluctuations modulate RNA dynamics in the SAM-I riboswitch.

Experiments demonstrate that Mg(2+) is crucial for structure and function of RNA systems, yet the detailed molecular mechanism of Mg(2+) action on RNA is not well understood. We investigate the interplay between RNA and Mg(2+) at atomic resolution through ten 2-µs explicit solvent molecular dynamics simulations of the SAM-I riboswitch with varying ion concentrations. The structure, including three stemloops, is very stable on this time scale. Simulations reveal that outer-sphere coordinated Mg(2+) ions fluctuate on the same time scale as the RNA, and that their dynamics couple. Locally, Mg(2+) association affects RNA conformation through tertiary bridging interactions; globally, increasing Mg(2+) concentration slows RNA fluctuations. Outer-sphere Mg(2+) ions responsible for these effects account for 80% of Mg(2+) in our simulations. These ions are transiently bound to the RNA, maintaining interactions, but shuttled from site to site. Outer-sphere Mg(2+) are separated from the RNA by a single hydration shell, occupying a thin layer 3-5 Å from the RNA. Distribution functions reveal that outer-sphere Mg(2+) are positioned by electronegative atoms, hydration layers, and a preference for the major groove. Diffusion analysis suggests transient outer-sphere Mg(2+) dynamics are glassy. Since outer-sphere Mg(2+) ions account for most of the Mg(2+) in our simulations, these ions may change the paradigm of Mg(2+)-RNA interactions. Rather than a few inner-sphere ions anchoring the RNA structure surrounded by a continuum of diffuse ions, we observe a layer of outer-sphere coordinated Mg(2+) that is transiently bound but strongly coupled to the RNA.

Role of large thermal fluctuations and magnesium ions in t-RNA selectivity of the ribosome.

The fidelity of translation selection begins with the base pairing of codon-anticodon complex between the m-RNA and tRNAs. Binding of cognate and near-cognate tRNAs induces 30S subunit of the ribosome to wrap around the ternary complex, EF-Tu(GTP)aa-tRNA. We have proposed that large thermal fluctuations play a crucial role in the selection process. To test this conjecture, we have developed a theoretical technique to determine the probability that the ternary complex, as a result of large thermal fluctuations, forms contacts leading to stabilization of the GTPase activated state. We argue that the configurational searches for such processes are in the tail end of the probability distribution and show that the probability for this event is localized around the most likely configuration. Small variations in the repositioning of cognate relative to near-cognate complexes lead to rate enhancement of the cognate complex. The binding energies of over a dozen unique site-bound magnesium structural motifs are investigated and provide insights into the nature of interaction of divalent metal ions with the ribosome.

Probing the alpha-helical structural stability of stapled p53 peptides: molecular dynamics simulations and analysis.

Reactivation of the p53 cell apoptosis pathway through inhibition of the p53-hDM2 interaction is a viable approach to suppress tumor growth in many human cancers and stabilization of the helical structure of synthetic p53 analogs via a hydrocarbon cross-link (staple) has been found to lead to increased potency and inhibition of protein-protein binding (J. Am. Chem. Soc. 129: 5298). However, details of the structure and dynamic stability of the stapled peptides are not well understood. Here, we use extensive all-atom molecular dynamics simulations to study a series of stapled alpha-helical peptides over a range of temperatures in solution. The peptides are found to exhibit substantial variations in predicted alpha-helical propensities that are in good agreement with the experimental observations. In addition, we find significant variation in local structural flexibility of the peptides with the position of the linker, which appears to be more closely related to the observed differences in activity than the absolute alpha-helical stability. These simulations provide new insights into the design of alpha-helical stapled peptides and the development of potent inhibitors of alpha-helical protein-protein interfaces.

Phospholipid reorientation at the lipid/water interface measured by high resolution 31P field cycling NMR spectroscopy.

The magnetic field dependence of the 31P spin-lattice relaxation rate, R1, of phospholipids can be used to differentiate motions for these molecules in a variety of unilamellar vesicles. In particular, internal motion with a 5- to 10-ns correlation time has been attributed to diffusion-in-a-cone of the phosphodiester region, analogous to motion of a cylinder in a liquid hydrocarbon. We use the temperature dependence of 31P R1 at low field (0.03-0.08 T), which reflects this correlation time, to explore the energy barriers associated with this motion. Most phospholipids exhibit a similar energy barrier of 13.2 +/- 1.9 kJ/mol at temperatures above that associated with their gel-to-liquid-crystalline transition (Tm); at temperatures below Tm, this barrier increases dramatically to 68.5 +/- 7.3 kJ/mol. This temperature dependence is broadly interpreted as arising from diffusive motion of the lipid axis in a spatially rough potential energy landscape. The inclusion of cholesterol in these vesicles has only moderate effects for phospholipids at temperatures above their Tm, but significantly reduces the energy barrier (to 17 +/- 4 kJ/mol) at temperatures below the Tm of the pure lipid. Very-low-field R1 data indicate that cholesterol inclusion alters the averaged disposition of the phosphorus-to-glycerol-proton vector (both its average length and its average angle with respect to the membrane normal) that determines the 31P relaxation.

The unique structure of A-tracts and intrinsic DNA bending.

Short runs of adenines are a ubiquitous DNA element in regulatory regions of many organisms. When runs of 4-6 adenine base pairs ('A-tracts') are repeated with the helical periodicity, they give rise to global curvature of the DNA double helix, which can be macroscopically characterized by anomalously slow migration on polyacrylamide gels. The molecular structure of these DNA tracts is unusual and distinct from that of canonical B-DNA. We review here our current knowledge about the molecular details of A-tract structure and its interaction with sequences flanking them of either side and with the environment. Various molecular models were proposed to describe A-tract structure and how it causes global deflection of the DNA helical axis. We review old and recent findings that enable us to amalgamate the various findings to one model that conforms to the experimental data. Sequences containing phased repeats of A-tracts have from the very beginning been synonymous with global intrinsic DNA bending. In this review, we show that very often it is the unique structure of A-tracts that is at the basis of their widespread occurrence in regulatory regions of many organisms. Thus, the biological importance of A-tracts may often be residing in their distinct structure rather than in the global curvature that they induce on sequences containing them.