Structure Of Energy Landscape Research Articles

Structural Energy Landscapes and Plasticity of the Microstates of Apo Escherichia coli cAMP Receptor Protein.

The theory for allostery has evolved to a modern energy landscape ensemble theory, the major feature of which is the existence of multiple microstates in equilibrium. The properties of microstates are not well defined due to their transient nature. Characterization of apo protein microstates is important because the specific complex of the ligand-bound microstate defines the biological function. The information needed to link biological function and structure is a quantitative correlation of the energy landscapes between the apo and holo protein states. We employed the Escherichia coli cAMP receptor protein (CRP) system to test the features embedded in the ensemble theory because multiple crystalline apo and holo structures are available. Small angle X-ray scattering data eliminated one of the three apo states but not the other two. We defined the underlying energy landscape differences among the apo microstates by employing the computation algorithm COREX/BEST. The same connectivity patterns among residues in apo CRP are retained upon binding of cAMP. The microstates of apo CRP differ from one another by minor structural perturbations, resulting in changes in the energy landscapes of the various domains of CRP. Using the differences in energy landscapes among these apo states, we computed the cAMP binding energetics that were compared with solution biophysical results. Only one of the three apo microstates yielded data consistent with the solution data. The relative magnitude of changes in energy landscapes embedded in various apo microstates apparently defines the ultimate outcome of the cooperativity of binding.

The structure-energy landscape of NMDA receptor gating.

N-methyl-D-aspartate (NMDA) receptors are the main calcium-permeable excitatory receptors in the mammalian central nervous system. The NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states; however, the central questions regarding the conformations and energetics of the transmembrane domains as they relate to the gating states are still unanswered. Here, using single molecule Förster Resonance Energy Transfer (smFRET), we map the energy landscape of the first transmembrane segment of the Rattus norvegicus NMDA receptor under resting and various liganded conditions. These results show kinetically and structurally distinct changes associated with apo, agonist-bound, and inhibited receptors linked by a linear mechanism of gating at this site. Furthermore, the smFRET data suggest that allosteric inhibition by zinc occurs by an uncoupling of the agonist-induced changes at the extracellular domains from the gating motions leading to an apo-like state, while dizocilpine, a pore blocker, stabilizes multiple closely packed transmembrane states.

Computationally-Guided Synthetic Control over Pore Size in Isostructural Porous Organic Cages.

The physical properties of 3-D porous solids are defined by their molecular geometry. Hence, precise control of pore size, pore shape, and pore connectivity are needed to tailor them for specific applications. However, for porous molecular crystals, the modification of pore size by adding pore-blocking groups can also affect crystal packing in an unpredictable way. This precludes strategies adopted for isoreticular metal–organic frameworks, where addition of a small group, such as a methyl group, does not affect the basic framework topology. Here, we narrow the pore size of a cage molecule, CC3, in a systematic way by introducing methyl groups into the cage windows. Computational crystal structure prediction was used to anticipate the packing preferences of two homochiral methylated cages, CC14-R and CC15-R, and to assess the structure–energy landscape of a CC15-R/CC3-S cocrystal, designed such that both component cages could be directed to pack with a 3-D, interconnected pore structure. The experimental gas sorption properties of these three cage systems agree well with physical properties predicted by computational energy–structure–function maps.

Intermolecular Interactions in Hybrid Perovskites Understood from a Combined Density Functional Theory and Effective Hamiltonian Approach

We show how the complex molecular structure of hybrid perovskites can be understood simply in terms of a few important intermolecular interactions. We deduce structural rules and coupling constants from an extensive density functional theory study of the structural energy landscape of methylammonium lead iodide. We have generated an unbiased structure–energy database, taking into account the orientations of molecular dipoles and inorganic lattice distortions. Analysis of this database shows that room-temperature structures are heavily dominated by a few hydrogen bonding patterns and lattice distortion modes. The molecule–molecule interactions, mediated by lattice distortions and hydrogen bonding, are shown to favor alignment of molecules at right angles to each other. We develop an effective Hamiltonian which shows that this interaction drives the cubic–tetragonal phase transition, explaining the temperature dependence of the tetragonal distortion observed in experiment.

Exploring polymorphism of benzene and naphthalene with free energy based enhanced molecular dynamics

Prediction and exploration of possible polymorphism in organic crystal compounds are of great importance for industries ranging from organic electronics to pharmaceuticals to high-energy materials. Here we apply our crystal structure prediction procedure and the enhanced molecular dynamics based sampling approach called the Crystal-Adiabatic Free Energy Dynamics (Crystal-AFED) method to benzene and naphthalene. Crystal-AFED allows the free energy landscape of structures to be explored efficiently at any desired temperature and pressure. For each system, we successfully predict the most stable crystal structures at atmospheric pressure and explore the relative Gibbs free energies of predicted polymorphs at high pressures. Using Crystal-AFED sampling, we find that mixed structures, which typically cannot be discovered by standard crystal structure prediction methods, are prevalent in the solid forms of these compounds at high pressure.

Anharmonic onsets in polypeptides revealed by neutron scattering: Experimental evidences and quantitative description of energy resolution dependence

Neutron scattering measurements on protein powders reveal two deviations from harmonic dynamics at low temperature, whose molecular origin, physical nature and biological relevance are still matter of discussion. In this study we present a new experimental and theoretical approach to evidence the resolution dependence of anharmonic onsets: the use of strategically selected homomeric polypeptides allows revealing the exact resolution dependence; a two-site energy landscape model, where resolution effects are explicitly taken into account, is able to interpret quantitatively the experimental data in terms of energy landscape parameters. The energetic description provided by this analysis, together with recent experimental evidences obtained on chemically and structurally different peptide systems, allows us to connect the protein/water energy landscape structure with the two-wells water interaction potential proposed to explain the low-density→high-density liquid–liquid transition observed in supercooled water.

Mortal Kombat: modeling amyloid fibrils and health implications

Amyloid proteins aggregate into polymorphic fibrils that damage tissues of the brain, nerves, and heart. Experimental and computational studies investigated the structural basis and the nucleation of short fibrils, but the prediction and the precise quantification of the stability of larger aggregates remain elusive. We established a complete classification of fibril shapes and developed a tool, called CreateFibril, to automatically build these complex polymorphic modular structures. CreateFibril constructed HET‐s, Abeta, and Amylin fibrils up to 17nm in length, and utilized a novel dipolar solvent model that captured the effect of dipole‐dipole interactions between water and very large molecular systems to assess their aqueous stability. Our results validated experimental data for HET‐s and Abeta, and suggested novel findings for Amylin. In particular, we predicted the correct structural parameters for the one and three predominant HET‐s protofilaments, revealed and structurally characterized all known Abeta polymorphic fibrils including structures recently classified as wrapped fibrils, and elucidated the predominant Amylin fibrils and asserted that native Amylin is more stable than its amyloid form. CreateFibril and a database of all stable polymorphic fibril models we tested along with their structural energy landscapes are available on http://amyloid.cs.mcgill.ca.

Computational Assembly of Polymorphic Amyloid Fibrils Reveals Stable Aggregates

Amyloid proteins aggregate into polymorphic fibrils that damage tissues of the brain, nerves, and heart. Experimental and computational studies have examined the structural basis and the nucleation of short fibrils, but the ability to predict and precisely quantify the stability of larger aggregates has remained elusive. We established a complete classification of fibril shapes and developed a tool called CreateFibril to build such complex, polymorphic, modular structures automatically. We applied stability landscapes, a technique we developed to reveal reliable fibril structural parameters, to assess fibril stability. CreateFibril constructed HET-s, Aβ, and amylin fibrils up to 17 nm in length, and utilized a novel dipolar solvent model that captured the effect of dipole-dipole interactions between water and very large molecular systems to assess their aqueous stability. Our results validate experimental data for HET-s and Aβ, and suggest novel (to our knowledge) findings for amylin. In particular, we predicted the correct structural parameters (rotation angles, packing distances, hydrogen bond lengths, and helical pitches) for the one and three predominant HET-s protofilaments. We reveal and structurally characterize all known Aβ polymorphic fibrils, including structures recently classified as wrapped fibrils. Finally, we elucidate the predominant amylin fibrils and assert that native amylin is more stable than its amyloid form. CreateFibril and a database of all stable polymorphic fibril models we tested, along with their structural energy landscapes, are available at http://amyloid.cs.mcgill.ca.

First-principles study of ferromagnetic Ni2CoGa(Zn) alloys in the Heusler and the inverse Heusler structure

AbstractWe performed an ab initio characterization of ferro- and nonmagnetic Ni2CoGa and Ni2CoZn compounds with respect to their potential application as new ferromagnetic shape memory alloys. The calculation of structural energy differences and mixing energies in the common X2YZ Heusler structure and the inverse (XY)XZ structure revealed, that both alloys are stable in the tetragonal distorted Heusler structure with a c/a ratio of 1.38 and show ferromagnetic ordering. The Curie temperatures are of the order of ≃ 250 K. Exchanging Ga with Zn improves the magnetic properties of the alloy without qualitative modification of the structural energy landscape, but at the expense of a reduced mixing energy.

Meta-Code for Systematic Analysis of Chemical Addition (SACHA): Application to Fluorination of C70 and Carbon Nanostructure Growth

We present a new computer program able to systematically study chemical addition to and growth or evolution of carbon nanostructures. SACHA is a meta-code able to exploit a wide variety of pre-existing molecular structure codes, automating the otherwise onerous task of constructing, running, and analyzing the large number of input files that are required when exploring structural isomers and addition paths. By way of examples we consider fluorination of the fullerene cage C70 and carbon nanostructure growth through C2 addition. We discuss the possibilities for extension of this technique to rapidly and efficiently explore structural energy landscapes and application to other areas of chemical and materials research.

Towards a theory for the mixed alkali effect in glasses

A general theoretical approach for the mixed alkali effect in glasses is discussed based on the idea that the covalent host network creates different structural energy landscapes for different types of mobile ions. By deriving a simplified model from this approach, it is shown how the experimentally observed changes in ion mobilities both upon mixing of two types of ions and upon changing the total concentration of mobile ions can be understood. Computer simulations of the model suggest that Coulomb forces have to be taken into account for explaining the differing behavior of activation energies in single modified and mixed ion glasses. It is further shown how the mixed alkali internal friction peak results from diffusional exchange processes of unlike ions in the glassy network.