Atomically detailed distributions of ions around an A-form RNA are computed. Different mixtures of monovalent and divalent ions are considered explicitly. Studies of tightly bound and of diffusive ...(but bound) ions around 25 base pairs RNA are conducted in explicit solvent. Replica exchange simulations provide detailed equilibrium distributions with moderate computing resources (20 ns of simulation using 64 replicas). The simulations show distinct behavior of single and double charged cations. Binding of Mg2+ ion includes tight binding to specific sites while Na + binds only diffusively. The tight binding of Mg2+ is with a solvation shell while Na + can bind directly to RNA. Negative mobile ions can be found near the RNA but must be assisted by proximate and mobile cations. At distances larger than 16 Å from the RNA center, a model of RNA as charged rod in a continuum of ionic solution provides quantitative description of the ion density (the same as in atomically detailed simulation). At shorter distances, the structure of RNA (and ions) has a significant impact on the pair correlation functions. Predicted binding sites of Mg2+ at the RNA surface are in accord with structures from crystallography. Electric field relaxation is investigated. The relaxation due to solution rearrangements is completed in tens of picoseconds, while the contribution of RNA tumbling continues to a few nanoseconds.
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Controlling the number of molecular switches and their relative positioning within porous materials is critical to their functionality and properties. The proximity of many molecular switches to one ...another can hinder or completely suppress their response. Herein, a synthetic strategy involving mixed linkers is used to control the distribution of spiropyran-functionalized linkers in a covalent organic framework (COF). The COF contains a spiropyran in each pore which exhibits excellent reversible photoswitching behavior to its merocyanine form in the solid state in response to UV/Vis light. The spiro-COF possesses an urchin-shaped morphology and exhibits a morphological transition to 2D nanosheets and vesicles in solution upon UV light irradiation. The merocyanine-equipped COFs are extremely stable and possess a more ordered structure with enhanced photoluminescence. This approach to modulating structural isomerization in the solid state is used to develop inkless printing media, while the photomediated polarity change is used for water harvesting applications.
The stability of RNA increases as the charge density of the alkali metal cations increases. The molecular mechanism for this phenomenon remains elusive. To fill this gap, we performed all-atom ...molecular dynamics pulling simulations of HIV-1 trans-activation response RNA. We first established that the free energy landscape obtained in the simulations is in excellent agreement with the single-molecule optical tweezer experiments. The origin of the stronger stability in sodium compared to potassium is found to be due to the differences in the charge density–related binding modes. The smaller hydrated sodium ion preferentially binds to the highly charged phosphates that have high surface area. In contrast, the larger potassium ions interact with the major grooves. As a result, more cations condense around phosphate groups in the case of sodium ions, leading to the reduction of electrostatic repulsion. Because the proposed mechanism is generic, we predict that the same conclusions are valid for divalent alkaline earth metal cations.
All-atom simulations of RNA unfolding highlight the critical role(s) played by charge density.
•Molecular dynamics based atomic model fitting into cryo-EM map is automated.•This automated program, cryo_fit, is integrated into the Phenix suite.•Cryo_fit enables larger conformational changes ...relative to rigid fitting and refinement.
Cryo-electron microscopy (cryo-EM) is becoming a method of choice for describing native conformations of biomolecular complexes at high resolution. The rapid growth of cryo-EM in recent years has created a high demand for automated solutions, both in hardware and software. Flexible fitting of atomic models to three-dimensional (3D) cryo-EM reconstructions by molecular dynamics (MD) simulation is a popular technique but often requires technical expertise in computer simulation. This work introduces cryo_fit, a package for the automatic flexible fitting of atomic models in cryo-EM maps using MD simulation. The package is integrated with the Phenix software suite. The module was designed to automate the multiple steps of MD simulation in a reproducible manner, as well as facilitate refinement and validation through Phenix. Through the use of cryo_fit, scientists with little experience in MD simulation can produce high quality atomic models automatically and better exploit the potential of cryo-EM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The biological role of biomolecules is intimately linked to their structural dynamics. Experimental or computational techniques alone are often insufficient to determine accurate structural ensembles ...in atomic detail. We use all-atom molecular dynamics (MD) simulations and couple it to small-angle X-ray scattering (SAXS) experiments to resolve the structural dynamics of RNA molecules. To accomplish this task, we utilize a set of re-weighting and biasing techniques tailored for RNA molecules. To showcase our approach, we study two RNA molecules: a riboswitch that shows structural variations upon ligand binding, and a two-way junction RNA that displays structural heterogeneity and sensitivity to salt conditions. Integration of MD simulations and experiments allows the accurate construction of conformational ensembles of RNA molecules. We observe a dynamic change of the SAM-I riboswitch conformations depending on its binding partners. The binding of SAM and Mg
2+
cations stabilizes the compact state. The absence of Mg
2+
or SAM leads to the loss of tertiary contacts, resulting in a dramatic expansion of the riboswitch conformations. The sensitivity of RNA structures to the ionic strength demonstrates itself in the helix junction helix (HJH). The HJH shows non-monotonic compaction as the ionic strength increases. The physics-based picture derived from the experimentally guided MD simulations allows biophysical characterization of RNA molecules. All in all, SAXS-guided MD simulations offer great prospects for studying RNA structural dynamics.
Chemical modification was used to quantitatively determine the flexibility of nearly the entire rRNA component of the yeast ribosome through 8 discrete stages of translational elongation, revealing ...novel observations at the gross and fine-scales. These include (i) the bulk transfer of energy through the intersubunit bridges from the large to the small subunit after peptidyltransfer, (ii) differences in the interaction of the sarcin ricin loop with the two elongation factors and (iii) networked information exchange pathways that may functionally facilitate intra- and intersubunit coordination, including the 5.8S rRNA. These analyses reveal hot spots of fluctuations that set the stage for large-scale conformational changes essential for translocation and enable the first molecular dynamics simulation of an 80S complex. Comprehensive datasets of rRNA base flexibilities provide a unique resource to the structural biology community that can be computationally mined to complement ongoing research toward the goal of understanding the dynamic ribosome.
The condensation of nucleic acids by lipids is a widespread phenomenon in biology with crucial implications for drug delivery. However, the mechanisms of DNA assembly in lipid bilayers remain ...insufficiently understood due to challenges in measuring and assessing each component’s contribution in the lipid–DNA–cation system. This study uses all-atom molecular dynamics simulations to investigate DNA condensation in cationic lipid bilayers. Our exhaustive exploration of the thermodynamic factors reveals unique roles for phospholipid head groups and cations. We observed that bridging cations between lipid and DNA drastically reduce charges, while mobile magnesium cations “ping-ponging” between double strands create charge fluctuations. While the first factor stabilizes the DNA–lipid complex, the latter creates attractive forces to induce the spontaneous condensation of DNAs. This novel mechanism not only sheds light on the current data regarding cationic lipid-induced DNA condensation but also provides potential design strategies for creating efficient gene delivery vectors for drug delivery.
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Inspired by the discovery of graphene and its unique properties, we focused our research to develop a scheme to create nacre like lamellar structures of molecular sheets of CaCO3 interleaved with an ...organic material, namely carbon. We developed a facile, chemical template technique, using a formulation of poly(acrylic) acid (PAA) and calcium acetate to create lamellar stacks of single crystal sheets of CaCO3, with a nominal thickness of 17 Å, the same as a unit-cell dimension for calcite (c-axis = 17.062 Å), interleaved with amorphous carbon with a nominal thickness of 8 Å. The strong binding affinity between carboxylate anions and calcium cations in the formulation was used as a molecular template to guide CaCO3 crystallization. Computational modeling of the FTIR spectra showed good agreement with experimental data and confirmed that calcium ions are bridged between polymer chains, resulting in a net-like polymer structure. The process readily lends itself to explore the feasibility of creating molecular sheets of other important inorganic materials and potentially find applications in many fields such as super capacitors and "low k di-electric" systems.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
An explosion of new data from high-resolution cryo-electron microscopy (cryo-EM) studies has produced a large number of data sets for many species of ribosomes in various functional states over the ...past few years. While many methods exist to produce structural models for lower resolution cryo-EM reconstructions, high-resolution reconstructions are often modeled using crystallographic techniques and extensive manual intervention. Here, we present an automated fitting technique for high-resolution cryo-EM data sets that produces all-atom models highly consistent with the EM density. Using a molecular dynamics approach, atomic positions are optimized with a potential that includes the cross-correlation coefficient between the structural model and the cryo-EM electron density, as well as a biasing potential preserving the stereochemistry and secondary structure of the biomolecule. Specifically, we use a hybrid structure-based/ab initio molecular dynamics potential to extend molecular dynamics fitting. In addition, we find that simulated annealing integration, as opposed to straightforward molecular dynamics integration, significantly improves performance. We obtain atomistic models of the human ribosome consistent with high-resolution cryo-EM reconstructions of the human ribosome. Automated methods such as these have the potential to produce atomistic models for a large number of ribosome complexes simultaneously that can be subsequently refined manually.
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