We present a molecular model for the adsorption of CO2, N2, H2, and their mixtures in dehydrated zeolite Na-4A. The interatomic potentials for this model were developed by comparing the results of grand canonical Monte Carlo (GCMC) simulations of single-component adsorption at room temperature with experimental measurements. GCMC simulation is also used to assess the adsorption selectivity of CO2/N2 and CO2/H2 mixtures, as a function of temperature and gas-phase composition. At room temperature, Na-4A is strongly selective for CO2 over both N2 and H2, although this selectivity decreases slightly as the gas-phase pressure increases. Ideal adsorbed solution theory is shown to give accurate predictions of the adsorption selectivity at low CO2 partial pressures, provided that a functional form that accurately describes the CO2 single-component isotherm is used. The adsorption properties of CO2/N2 mixtures in Na-4A are compared to the same mixtures in silicalite.

BackgroundTo understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human β2-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K.ResultsAfter around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies.ConclusionsThe essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes.

BackgroundThis study investigates the allosteric coupling that exists between the intra- and extracellular parts of human β2-adrenergic receptor (β2-AR), in the presence of the intracellular loop 3 (ICL3), which is missing in all crystallographic experiments and most of the simulation studies reported so far. Our recent 1 μs long MD run has revealed a transition to the so-called very inactive state of the receptor, in which ICL3 packed under the G protein’s binding cavity and completely blocked its accessibility to G protein. Simultaneously, an outward tilt of transmembrane helix 5 (TM5) caused an expansion of the extracellular ligand-binding site. In the current study, we performed independent runs with a total duration of 4 μs to further investigate the very inactive state with packed ICL3 and the allosteric coupling event (three unrestrained runs and five runs with bond restraints at the ligand-binding site).ResultsIn all three independent unrestrained runs (each 500 ns long), ICL3 preserved its initially packed/closed conformation within the studied time frame, suggesting an inhibition of the receptor’s activity. Specific bond restraints were later imposed between some key residues at the ligand-binding site, which have been experimentally determined to interact with the ligand. Restraining the binding site region to an open state facilitated ICL3 closure, whereas a relatively constrained/closed binding site hindered ICL3 packing. However, the reverse operation, i.e. opening of the packed ICL3, could not be realized by restraining the binding site region to a closed state. Thus, any attempt failed to free the ICL3 from its locked state due to the presence of persistent hydrogen bonds.ConclusionsOverall, our simulations indicated that starting with very inactive states, the receptor stayed almost irreversibly inhibited, which in turn decreased the overall mobility of the receptor. Bond restraints which represented the geometric restrictions caused by ligands of various sizes when bound at the ligand-binding site, induced the expected conformational changes in TM5, TM6 and consequently, ICL3. Still, once ICL3 was packed, the allosteric coupling became ineffective due to strong hydrogen bonds connecting ICL3 to the core of the receptor.Electronic supplementary materialThe online version of this article (doi:10.1186/s12900-016-0061-9) contains supplementary material, which is available to authorized users.

The tunnel region at triosephosphate isomerase (TIM)'s dimer interface, distant from its catalytic site, is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi, the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor, named bt10. Within the time frame of our MD simulations, we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10, which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54,000 MD snapshots. Using this computationally efficient technique, we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly, we observed allosteric changes in the catalytic loop's dynamics, flexibility, and correlations, as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme.

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Simulations have been performed at 473 K for one-component melts of polyethylene (PE) and head-to-head, tail-to-tail polypropylene (hhPP) as well as a mixture of the two species. The densities are 0.760, 0.753, and 0.756 g/cm 3 for these three NVT simulations, respectively. The Monte Carlo simulation uses coarse-grained representations of the chains on a sparsely occupied high coordination lattice. The short-range intramolecular interactions are controlled by rotational isomeric state models for the two types of chains, and the intermolecular interactions are represented by a discretized version of Lennard-Jones potential energy functions. Equilibrated coarse-grained replicas are reverse-mapped to atomistically detailed models in continuous space. The pair correlation functions clearly demonstrate the onset of demixing for the two-component melt, which is qualitatively consistent with the conclusion from small-angle neutron scattering reported by Jeon et al. [Macromolecules 1998, 31, 3340]. Analysis of the components of the energy in the simulations shows that the positive energy change on mixing is completely dominated by the intermolecular Lennard-Jones contributions, with negligible contributions from the short-range intramolecular interactions in the rotational isomeric state models. Quantitative comparison with experiment shows that the χ deduced from the simulations is larger than the χ deduced from the experiments. Several factors in the experiments and in the simulations may contribute to the quantitative difference.

We aim to uncover the binding modes of benzothiazoles, which have been reported as specific inhibitors of triosephosphate isomerase from the parasite Trypanosoma cruzi (TcTIM), by performing blind dockings on both TcTIM and human TIM (hTIM). Detailed analysis of binding sites and specific interactions are carried out based on ensemble dockings to multiple receptor conformers obtained from molecular dynamics simulations. In TcTIM dimer dockings, the inhibitors preferentially bind to the tunnel-shaped cavity formed at the interface of the subunits, whereas non-inhibitors mostly choose other sites. In contrast, TcTIM monomer binding interface and hTIM dimer interface do not present a specific binding site for the inhibitors. These findings point to the importance of the tunnel and of the dimeric form for inhibition of TcTIM. Specific interactions of the inhibitors and their sulfonate-free derivatives with the receptor residues indicate the significance of sulfonate group for binding affinity and positioning on the TcTIM dimer interface. One of the inhibitors also binds to the active site, which may explain its relatively higher inhibition effect on hTIM.

Anisotropic network model is used to generate a set of distinct conformations for cylophilin A (CypA). The native structure is deformed to different extents along each of the lowest-frequency modes (first 7 modes) both in negative and positive directions. Each node of the elastic network represents either a single atom in the high-resolution model or a single residue in the low-resolution model. Realistic conformations with energies close to or lower than the crystal structure and with satisfactory internal geometry are recovered by energy minimization using implicit solvation model. These conformations are then used for ensemble docking to the ligand cyclosporin A for both a further test of accuracy of generated conformers and exploration of different binding modes. Higher number of correctly docked ligands are obtained for conformations with low deformation factors as a result of lower root mean square distances with respect to crystal structure. Yet, surprisingly, the lowest binding energy is obtained for one of the highly deformed conformations as a result of its special contact with arginine side chain oriented towards binding site. Considering the fact that the cyclic ligand's backbone and protein's side chains are held rigid during docking, the conformers generated by high- and low-resolution elastic network models are almost equally successful in providing the correct binding mode. The shape of the binding pocket that incorporates crucial interaction sites for hydrogen bond formation is found to be another important determining factor for the success of the dock. Also, the small backbone variations of a few Angstroms in magnitude at the loop regions surrounding the binding pocket can cause amino acids' side chains to be displaced by magnitudes of up to 10 A and therefore have a strong influence on the efficiency of the conformational search during docking.