GABA receptor associated protein changes the electrostatic environment around the GABA type A receptor.

We have performed fully atomistic molecular dynamics simulations of the intracellular domain of a model of the GABAA receptor with and without the GABA receptor associated protein (GABARAP) bound. We have also calculated the electrostatic potential due to the receptor, in the absence and presence of GABARAP. We find that GABARAP binding changes the electrostatic properties around the GABAA receptor and could lead to increased conductivity of chloride ions through the receptor. We also find that ion motions that would result in conducting currents are observed nearly twice as often when GABARAP binds. These results are consistent with data from electrophysiological experiments.

Modeling Pair Distribution Functions of Rare-Earth Phosphate Glasses Using Principal Component Analysis.

The use of principal component analysis (PCA) to statistically infer features of local structure from experimental pair distribution function (PDF) data is assessed on a case study of rare-earth phosphate glasses (REPGs). Such glasses, codoped with two rare-earth ions (R and R') of different sizes and optical properties, are of interest to the laser industry. The determination of structure-property relationships in these materials is an important aspect of their technological development. Yet, realizing the local structure of codoped REPGs presents significant challenges relative to their singly doped counterparts; specifically, R and R' are difficult to distinguish in terms of establishing relative material compositions, identifying atomic pairwise correlation profiles in a PDF that are associated with each ion, and resolving peak overlap of such profiles in PDFs. This study demonstrates that PCA can be employed to help overcome these structural complications, by statistically inferring trends in PDFs that exist for a restricted set of experimental data on REPGs, and using these as training data to predict material compositions and PDF profiles in unknown codoped REPGs. The application of these PCA methods to resolve individual atomic pairwise correlations in t(r) signatures is also presented. The training methods developed for these structural predictions are prevalidated by testing their ability to reproduce known physical phenomena, such as the lanthanide contraction, on PDF signatures of the structurally simpler singly doped REPGs. The intrinsic limitations of applying PCA to analyze PDFs relative to the quality control of source data, data processing, and sample definition, are also considered. While this case study is limited to lanthanide-doped REPGs, this type of statistical inference may easily be extended to other inorganic solid-state materials and be exploited in large-scale data-mining efforts that probe many t(r) functions.

Does water dope carbon nanotubes?

We calculate the long-range perturbation to the electronic charge density of carbon nanotubes (CNTs) as a result of the physisorption of a water molecule. We find that the dominant effect is a charge redistribution in the CNT due to polarisation caused by the dipole moment of the water molecule. The charge redistribution is found to occur over a length-scale greater than 30 Å, highlighting the need for large-scale simulations. By comparing our fully first-principles calculations to ones in which the perturbation due to a water molecule is treated using a classical electrostatic model, we estimate that the charge transfer between CNT and water is negligible (no more than 10(-4) e per water molecule). We therefore conclude that water does not significantly dope CNTs, a conclusion that is consistent with the poor alignment of the relevant energy levels of the water molecule and CNT. Previous calculations that suggest water n-dopes CNTs are likely due to the misinterpretation of Mulliken charge partitioning in small supercells.

Efficiently Differentiating Agonists and Competitive Antagonists for Weak Allosteric Protein-Ligand Interactions with Linear Response Theory.

What makes an agonist and a competitive antagonist? In this work, we aim to answer this question by performing parallel tempering Monte Carlo simulations on the serotonin type 3A (5-HT3A) receptor. We use linear response theory to predict conformational changes in the 5-HT3A receptor active site after weak perturbations are applied to its allosteric binding sites. A covariance tensor is built from conformational sampling of its apo state, and a harmonic approximation allows us to substitute the calculation of ligand-induced forces with the binding site's displacement vector. Remarkably, our study demonstrates the feasibility of effectively discerning between agonists and competitive antagonists for multiple ligands, requiring computationally expensive calculations only once per protein.

PrP conformational transitions alter species preference of a PrP-specific antibody.

The epitope of the 3F4 antibody most commonly used in human prion disease diagnosis is believed to consist of residues Met-Lys-His-Met (MKHM) corresponding to human PrP-(109-112). This assumption is based mainly on the observation that 3F4 reacts with human and hamster PrP but not with PrP from mouse, sheep, and cervids, in which Met at residue 112 is replaced by Val. Here we report that, by brain histoblotting, 3F4 did not react with PrP of uninfected transgenic mice expressing elk PrP; however, it did show distinct immunoreactivity in transgenic mice infected with chronic wasting disease. Compared with human PrP, the 3F4 reactivity with the recombinant elk PrP was 2 orders of magnitude weaker, as indicated by both Western blotting and surface plasmon resonance. To investigate the molecular basis of these species- and conformer-dependent preferences of 3F4, the epitope was probed by peptide membrane array and antigen competition experiments. Remarkably, the 3F4 antibody did not react with MKHM but reacted strongly with KTNMK (corresponding to human PrP-(106-110)), a sequence that is also present in cervids, sheep, and cattle. 3F4 also reacted with elk PrP peptides containing KTNMKHV. We concluded that the minimal sequence for the 3F4 epitope consists of residues KTNMK, and the species- and conformer-dependent preferences of 3F4 arise largely from the interactions between Met(112) (human PrP) or Val(115) (cervid PrP) and adjacent residues.

Modeling Molecular Emitters in Organic Light-Emitting Diodes with the Quantum Mechanical Bespoke Force Field.

Combined molecular dynamics (MD) and quantum mechanics (QM) simulation procedures have gained popularity in modeling the spectral properties of functional organic molecules. However, the potential energy surfaces used to propagate long-time scale dynamics in these simulations are typically described using general, transferable force fields designed for organic molecules in their electronic ground states. These force fields do not typically include spectroscopic data in their training, and importantly, there is no general protocol for including changes in geometry or intermolecular interactions with the environment that may occur upon electronic excitation. In this work, we show that parameters tailored for thermally activated delayed fluorescence (TADF) emitters used in organic light-emitting diodes (OLEDs), in both their ground and electronically excited states, can be readily derived from a small number of QM calculations using the QUBEKit (QUantum mechanical BEspoke toolKit) software and improve the overall accuracy of these simulations.

ONETEP + TOSCAM: Uniting Dynamical Mean Field Theory and Linear-Scaling Density Functional Theory.

We introduce the unification of dynamical mean field theory (DMFT) and linear-scaling density functional theory (DFT), as recently implemented in ONETEP, a linear-scaling DFT package, and TOSCAM, a DMFT toolbox. This code can account for strongly correlated electronic behavior while simultaneously including the effects of the environment, making it ideally suited for studying complex and heterogeneous systems that contain transition metals and lanthanides, such as metalloproteins. We systematically introduce the necessary formalism, which must account for the nonorthogonal basis set used by ONETEP. In order to demonstrate the capabilities of this code, we apply it to carbon monoxide ligated iron porphyrin and explore the distinctly quantum-mechanical character of the iron 3d electrons during the process of photodissociation.

Development and Validation of the Quantum Mechanical Bespoke Protein Force Field.

Molecular mechanics force field parameters for macromolecules, such as proteins, are traditionally fit to reproduce experimental properties of small molecules, and thus, they neglect system-specific polarization. In this paper, we introduce a complete protein force field that is designed to be compatible with the quantum mechanical bespoke (QUBE) force field by deriving nonbonded parameters directly from the electron density of the specific protein under study. The main backbone and sidechain protein torsional parameters are rederived in this work by fitting to quantum mechanical dihedral scans for compatibility with QUBE nonbonded parameters. Software is provided for the preparation of QUBE input files. The accuracy of the new force field, and the derived torsional parameters, is tested by comparing the conformational preferences of a range of peptides and proteins with experimental measurements. Accurate backbone and sidechain conformations are obtained in molecular dynamics simulations of dipeptides, with NMR J coupling errors comparable to the widely used OPLS force field. In simulations of five folded proteins, the secondary structure is generally retained, and the NMR J coupling errors are similar to standard transferable force fields, although some loss of the experimental structure is observed in certain regions of the proteins. With several avenues for further development, the use of system-specific nonbonded force field parameters is a promising approach for next-generation simulations of biological molecules.

Large-Scale Study of Hydration Environments through Hydration Sites.

Hydration sites are locations of interest to water and they can be used to classify the behavior of water around chemical motifs commonly found on the surface of proteins. Inhomogeneous fluid solvation theory (IFST) is a method for calculating hydration free-energy changes from molecular dynamics (MD) trajectories. In this paper, hydration sites are identified from MD simulations of 380 diverse protein structures. The hydration free energies of the hydration sites are calculated using IFST and distributions of these free-energy changes are analyzed. The results show that for some hydration sites near features conventionally regarded as attractive to water, such as hydrogen bond donors, the water molecules are actually relatively weakly bound and are easily displaced. We also construct plots of the spatial density of hydration sites with high, medium, and low hydration free-energy changes which represent weakly and strongly bound hydration sites. It is found that these plots show consistent features around common polar amino acids for all of the proteins studied.

Harmonic Force Constants for Molecular Mechanics Force Fields via Hessian Matrix Projection.

A modification to the Seminario method [ Int. J. Quantum Chem. 1996 , 60 , 1271 - 1277 ] is proposed, which derives accurate harmonic bond and angle molecular mechanics force field parameters directly from the quantum mechanical Hessian matrix. The new method reduces the average error in the reproduction of quantum mechanical normal-mode frequencies of a benchmark set of 70 molecules from 12.3% using the original method, to 6.3%. The modified Seminario method is fully automated, and all parameters are computed directly from quantum mechanical data, thereby avoiding interdependency between bond and angle parameters and other components of the force field. A complete set of bond and angle force field parameters for the 20 naturally occurring amino acids is also provided for use in the future development of protein force fields.

Evidence of Correlated Static Disorder in the Fenna-Matthews-Olson Complex.

Observation of excitonic quantum beats in photosynthetic antennae has prompted wide debate regarding the function of excitonic coherence in pigment-protein complexes. Much of this work focuses on the interactions of excitons with the femto-to-picosecond dynamical fluctuations of their environment. However, in experiments these effects can be masked by static disorder of the excited-state energies across ensembles, whose microscopic origins are challenging to predict. Here the excited-state properties of ∼2000 atom clusters of the Fenna-Matthews-Olson complex are simulated using a unique combination of linear-scaling density functional theory and constrained geometric dynamics. While slow, large amplitude protein motion leads to large variations in the Qy transitions of two pigments, we identify pigment-protein correlations that greatly reduce variations in the energy gap across the ensemble, which is consistent with experimental observations of suppressed inhomogeneous dephasing of quantum beats.

New insights into the origin of visible light photocatalytic activity of nitrogen-doped and oxygen-deficient anatase TiO2.

The spin-polarized plane-wave pseudopotential method, based on density-functional theory, has been used to calculate the electronic band structures and the optical absorption spectra of nitrogen-doped and oxygen-deficient anatase TiO2. The calculated results are in good agreement with our experimental measurements. These ab initio calculations reveal that the optical absorption of nitrogen-doped TiO2 in the visible light region is primarily located between 400 and 500 nm, while that of oxygen-deficient TiO2 is mainly above 500 nm. These results have important implications for the understanding and further development of photocatalytic materials that are active under visible light.

Spin filtering and magneto-resistive effect at the graphene/h-BN ribbon interface.

Advances in the realization of hybrid graphene/h-BN materials open new ways to control the electronic properties of graphene nanostructures. In this paper, the structural, electronic, and transport properties of heterojunctions made of bare zigzag-shaped h-BN and graphene ribbons are investigated using first-principles techniques. Our results highlight the potential of graphene/h-BN junctions for applications in spintronic devices. At first, density functional theory is used to detail the role played by the edge states and dangling bonds in the electronic and magnetic behavior of h-BN and graphene ribbons. Then, the electronic conductance of the junction is computed in the framework of Green's function-based scattering theory. In its high-spin configuration, the junction reveals a full spin polarization of the propagating carriers around the Fermi energy, and the magnitude of the transmission probability is predicted to be strongly dependent on the relative orientation of magnetic momenta in the leads.

Myosin phosphatase isoform switching in vascular smooth muscle development.

We are using the myosin phosphatase targeting subunit (MYPT1) as a model gene to study smooth muscle phenotypic diversity. Myosin phosphatase (MP) is the primary effector of smooth muscle relaxation, and MYPT1 is a key target of signals that regulate smooth muscle tone. In a model of portal hypertension we previously showed dynamic changes in the expression of MYPT1 isoforms in the portal vein and upstream mesenteric artery. We hypothesized that this represents a reversion to the fetal phenotype characteristic of muscle hypertrophy. Here we studied MP during vascular smooth muscle phenotypic specification. Between postnatal days 6 and 12 the expression of MYPT1 increased approximately twofold in portal vein with a similar increase in MP activity. MYPT1 switched from C-terminal leucine zipper (LZ) positive to LZ negative splice variant isoforms. This was concordant with a switch from sensitive (10(-7) M) to resistant to cGMP-mediated vascular relaxation. This is consistent with the model in which the MYPT1 C-terminal LZ is required for cGMP-dependent activation of MP. Concordant changes in the expression of other contractile proteins were consistent with a switch from a slow-tonic to a fast-phasic contractile phenotype. In contrast aortic smooth muscle throughout development expressed the MYPT1 LZ positive isoform and relaxed to cGMP. We propose that MP isoform switching during neonatal vascular smooth muscle phenotypic specification may determine changing vascular responses to NO/cGMP signaling in the transition from the fetal to the adult circulation.

Chemically active substitutional nitrogen impurity in carbon nanotubes.

We investigate the nitrogen substitutional impurity in semiconducting zigzag and metallic armchair single-wall carbon nanotubes using ab initio density functional theory. At low concentrations (less than 1 at. %), the defect state in a semiconducting tube becomes spatially localized and develops a flat energy level in the band gap. Such a localized state makes the impurity site chemically and electronically active. We find that if two neighboring tubes have their impurities facing one another, an intertube covalent bond forms. This finding opens an intriguing possibility for tunnel junctions, as well as the functionalization of suitably doped carbon nanotubes by selectively forming chemical bonds with ligands at the impurity site. If the intertube bond density is high enough, a highly packed bundle of interlinked single-wall nanotubes can form.

Dynamic changes in expression of myosin phosphatase in a model of portal hypertension.

Myosin phosphatase is a target for signaling pathways that modulate calcium sensitivity of force production in smooth muscle. Myosin phosphatase targeting subunit 1 (MYPT1) isoforms are generated by cassette-type alternative splicing of exons in the central and 3' portion of the transcript. Exclusion of the 3' alternative exon, coding for the leucine zipper (LZ)-positive MYPT1 isoform, is associated with the ability to desensitize to calcium (relax) in response to NO/cGMP-dependent signaling. We examined expression of MYPT1 isoforms and smooth muscle phenotype in normal rat vessels and in a prehepatic model of portal hypertension characterized by arteriolar dilation. The large capacitance vessels, aorta, pulmonary artery, and inferior vena cava expressed predominantly the 3' exon-out/LZ-positive MYPT1 isoform. The first-order mesenteric resistance artery (MA1) and portal vein (PV) expressed severalfold higher levels of MYPT1 with predominance of the 3' exon-included/LZ-negative isoform. There was minor variation in the presence of the MYPT1 central alternative exons. Myosin heavy and light chain splice variants in part cosegregated with MYPT1 isoforms. In response to portal hypertension induced by PV ligature, abundance of MYPT1 in PV and MA1 was significantly reduced and switched to the LZ-positive isoform. These changes were evident within 1 day of PV ligature and were maintained for up to 10 days before reverting to control values at day 14. Alteration of MYPT1 expression was part of a complex change in protein expression that can be generalized as a modulation from a phasic (fast) to a tonic (slow) contractile phenotype. Implications of vascular smooth muscle phenotypic diversity and reversible phenotypic modulation in portal hypertension with regards to regulation of blood flow are discussed.