Modulation of Structure and Dynamics of Cardiac Troponin by Phosphorylation and Mutations Revealed by Molecular Dynamics Simulations.

Adrenaline acts on β1 receptors in the heart muscle to enhance contractility, increase the heart rate, and increase the rate of relaxation (lusitropy) via activation of the cyclic AMP-dependent protein kinase, PKA. Phosphorylation of serines 22 and 23 in the N-terminal peptide of cardiac troponin I is responsible for lusitropy. Mutations associated with cardiomyopathy suppress the phosphorylation-dependent change.

Kinetics and Mechanisms of Hydrothermal Dehydration of Cyclic 1,2- and 1,4-Diols.

Hydrothermal dehydration is an attractive method for deoxygenation and upgrading of biofuels because it requires no reagents or catalysts other than superheated water. Although mono-alcohols cleanly deoxygenate via dehydration under many conditions, polyols such as those derived from saccharides and related structures are known to be recalcitrant with respect to dehydration. Here, we describe detailed mechanistic and kinetic studies of hydrothermal dehydration of 1,2- and 1,4-cyclohexanediols as model compounds to investigate how interactions between the hydroxyls can control the reaction.

Large-Scale Distributed Training of Transformers for Chemical Fingerprinting.

Transformer models have become a popular choice for various machine learning tasks due to their often outstanding performance. Recently, transformers have been used in chemistry for classifying reactions, reaction prediction, physiochemical property prediction, and more. These models require huge amounts of data and localized compute to train effectively.

Modulation of cardiac thin filament structure by phosphorylated troponin-I analyzed by protein-protein docking and molecular dynamics simulation.

Tropomyosin, controlled by troponin-linked Ca-binding, regulates muscle contraction by a macromolecular scale steric-mechanism that governs myosin-crossbridge-actin interactions. At low-Ca, C-terminal domains of troponin-I (TnI) trap tropomyosin in a position on thin filaments that interferes with myosin-binding, thus causing muscle relaxation. Steric inhibition is reversed at high-Ca when TnI releases from F-actin-tropomyosin as Ca and the TnI switch-peptide bind to the N-lobe of troponin-C (TnC).

Lipid21: Complex Lipid Membrane Simulations with AMBER.

We extend the modular AMBER lipid force field to include anionic lipids, polyunsaturated fatty acid (PUFA) lipids, and sphingomyelin, allowing the simulation of realistic cell membrane lipid compositions, including raft-like domains. Head group torsion parameters are revised, resulting in improved agreement with NMR order parameters, and hydrocarbon chain parameters are updated, providing a better match with phase transition temperature. Extensive validation runs (0.

Design, synthesis and evaluation of a tripodal receptor for phosphatidylinositol phosphates.

Phosphatidylinositol phosphates (PIPs) are membrane phospholipids that play crucial roles in a wide range of cellular processes. Their function is dictated by the number and positions of the phosphate groups in the inositol ring (with seven different PIPs being active in the cell). Therefore, there is significant interest in developing small-molecule receptors that can bind selectively to these species and in doing so affect their cellular function or be the basis for molecular probes.

A TDDFT investigation of the Photosystem II reaction center: Insights into the precursors to charge separation.

Photosystem II (PS II) captures solar energy and directs charge separation (CS) across the thylakoid membrane during photosynthesis. The highly oxidizing, charge-separated state generated within its reaction center (RC) drives water oxidation. Spectroscopic studies on PS II RCs are difficult to interpret due to large spectral congestion, necessitating modeling to elucidate key spectral features.

Understanding the Solvent Contribution to Chemical Reaction Barriers.

Absolute rate theories attempt to predict the rate constants of reactions from basic principles and independent data. For the contribution of solvent to a reaction rate constant, this requires connecting absolute rate data to fundamental solvent properties such as dielectric constant and refractive index. We have explored this connection for the unimolecular fragmentation reaction of a pinacol radical cation.

Mechanism of Photoinduced Triplet Intermolecular Hydrogen Transfer between Cycloxydim and Chlorothalonil.

The possible reaction mechanisms for the experimentally observed hydrogen transfer between the herbicide cycloxydim (CD) and the triplet fungicide chlorothalonil (CT) were identified with density functional theory (DFT) and time-dependent density function theory (TDDFT) computations. Excited energy transfer (EET) calculations indicate that reactants for intermolecular hydrogen transfer were formed via energy transfer from triplet CT to ground state CD. Three possible reaction pathways after EET were identified, and hydrogen transfer from the hydroxyl group on the cyclohexane ring of CD to CT exhibited the lowest energy barrier.

Imaging plasma membrane phase behaviour in live cells using a thiophene-based molecular rotor.

Molecular rotors have emerged as versatile probes of microscopic viscosity in lipid bilayers, although it has proved difficult to find probes that stain both phases equally in phase-separated bilayers. Here, we investigate the use of a membrane-targeting viscosity-sensitive fluorophore based on a thiophene moiety with equal affinity for ordered and disordered lipid domains to probe ordering and viscosity within artificial lipid bilayers and live cell plasma membranes.

Molecular dynamics studies on the DNA-binding process of ERG.

The ETS family of transcription factors regulate gene targets by binding to a core GGAA DNA-sequence. The ETS factor ERG is required for homeostasis and lineage-specific functions in endothelial cells, some subset of haemopoietic cells and chondrocytes; its ectopic expression is linked to oncogenesis in multiple tissues. To date details of the DNA-binding process of ERG including DNA-sequence recognition outside the core GGAA-sequence are largely unknown.

Troponin structure: its modulation by Ca(2+) and phosphorylation studied by molecular dynamics simulations.

The only available crystal structure of the human cardiac troponin molecule (cTn) in the Ca(2+) activated state does not include crucial segments, including the N-terminus of the cTn inhibitory subunit (cTnI). We have applied all-atom molecular dynamics (MD) simulations to study the structure and dynamics of cTn, both in the unphosphorylated and bis-phosphorylated states at Ser23/Ser24 of cTnI. We performed multiple microsecond MD simulations of wild type (WT) cTn (6, 5 μs) and bisphosphorylated (SP23/SP24) cTn (9 μs) on a 419 amino acid cTn model containing human sequence cTnC (1-161), cTnI (1-171) and cTnT (212-298), including residues not present in the crystal structure.

Simulation of lipid bilayer self-assembly using all-atom lipid force fields.

In this manuscript we expand significantly on our earlier communication by investigating the bilayer self-assembly of eight different types of phospholipids in unbiased molecular dynamics (MD) simulations using three widely used all-atom lipid force fields. Irrespective of the underlying force field, the lipids are shown to spontaneously form stable lamellar bilayer structures within 1 microsecond, the majority of which display properties in satisfactory agreement with the experimental data. The lipids self-assemble via the same general mechanism, though at formation rates that differ both between lipid types, force fields and even repeats on the same lipid/force field combination.

Reversible Electrochemical Trapping of Carbon Dioxide Using 4,4'-Bipyridine That Does Not Require Thermal Activation.

Sequestering carbon dioxide emissions by the trap and release of CO2 via thermally activated chemical reactions has proven problematic because of the energetic requirements of the release reactions. Here we demonstrate trap and release of carbon dioxide using electrochemical activation, where the reactions in both directions are exergonic and proceed rapidly with low activation barriers. One-electron reduction of 4,4'-bipyridine forms the radical anion, which undergoes rapid covalent bond formation with carbon dioxide to form an adduct.

Organic Oxidations Using Geomimicry.

Oxidations of phenylacetic acid to benzaldehyde, benzyl alcohol to benzaldehyde, and benzaldehyde to benzoic acid have been observed, in water as the solvent and using only copper(II) chloride as the oxidant. The reactions are performed at 250 °C and 40 bar, conditions that mimic hydrothermal reactions that are geochemically relevant. Speciation calculations show that the oxidizing agent is not freely solvated copper(II) ions, but complexes of copper(II) with chloride and carboxylate anions.

A Parameterization of Cholesterol for Mixed Lipid Bilayer Simulation within the Amber Lipid14 Force Field.

The Amber Lipid14 force field is expanded to include cholesterol parameters for all-atom cholesterol and lipid bilayer molecular dynamics simulations. The General Amber and Lipid14 force fields are used as a basis for assigning atom types and basic parameters. A new RESP charge derivation for cholesterol is presented, and tail parameters are adapted from Lipid14 alkane tails.

Imaging phase separation in model lipid membranes through the use of BODIPY based molecular rotors.

In order to fully understand the dynamics of processes within biological lipid membranes, it is necessary to possess an intimate knowledge of the physical state and ordering of lipids within the membrane. Here we report the use of three molecular rotors based on meso-substituted boron-dipyrrin (BODIPY) in combination with fluorescence lifetime spectroscopy to investigate the viscosity and phase behaviour of model lipid bilayers. In phase-separated giant unilamellar vesicles, we visualise both liquid-ordered (Lo) and liquid-disordered (Ld) phases using fluorescence lifetime imaging microscopy (FLIM), determining their associated viscosity values, and investigate the effect of composition on the viscosity of these phases.

All-atom lipid bilayer self-assembly with the AMBER and CHARMM lipid force fields.

This communication reports the first example of spontaneous lipid bilayer formation in unbiased all-atom molecular dynamics (MD) simulations. Using two different lipid force fields we show simulations started from random mixtures of lipids and water in which four different types of phospholipids self-assemble into organized bilayers in under 1 microsecond.

Sphalerite is a geochemical catalyst for carbon-hydrogen bond activation.

Reactions among minerals and organic compounds in hydrothermal systems are critical components of the Earth's deep carbon cycle, provide energy for the deep biosphere, and may have implications for the origins of life. However, there is limited information as to how specific minerals influence the reactivity of organic compounds. Here we demonstrate mineral catalysis of the most fundamental component of an organic reaction: the breaking and making of a covalent bond.

Hydrothermal photochemistry as a mechanistic tool in organic geochemistry: the chemistry of dibenzyl ketone.

Hydrothermal organic transformations under geochemically relevant conditions can result in complex product mixtures that form via multiple reaction pathways. The hydrothermal decomposition reactions of the model ketone dibenzyl ketone form a mixture of reduction, dehydration, fragmentation, and coupling products that suggest simultaneous and competitive radical and ionic reaction pathways. Here we show how Norrish Type I photocleavage of dibenzyl ketone can be used to independently generate the benzyl radicals previously proposed as the primary intermediates for the pure hydrothermal reaction.

Lipid14: The Amber Lipid Force Field.

The AMBER lipid force field has been updated to create Lipid14, allowing tensionless simulation of a number of lipid types with the AMBER MD package. The modular nature of this force field allows numerous combinations of head and tail groups to create different lipid types, enabling the easy insertion of new lipid species. The Lennard-Jones and torsion parameters of both the head and tail groups have been revised and updated partial charges calculated.

N-alkoxyheterocycles as irreversible photooxidants.

Irreversible photooxidation based on N-O bond fragmentation is demonstrated for N-methoxyheterocycles in both the singlet and triplet excited state manifolds. The energetic requirements for bond fragmentation are studied in detail. Bond fragmentation in the excited singlet manifold is possible for ππ* singlet states with energies significantly larger than the N-O bond dissociation energy of ca 55 kcal mol(-1).

Understanding the relative affinity and specificity of the pleckstrin homology domain of protein kinase B for inositol phosphates.

Protein kinase B (PKB) is a serine/threonine kinase that plays a key role in the phosphoinositide 3-kinase (PI3K) pathway-one of the most frequently activated proliferation pathways in cancer. In this pathway, PKB is recruited to the plasma membrane by direct interaction of its pleckstrin homology (PH) domain with the inositol phosphate head-group of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] or phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P(2)]. This recruitment is a critical stage in the activation of PKB, whose downstream effectors play important roles in cell survival, proliferation and growth.

Further evaluation of quantum chemical methods for the prediction of non-specific binding of positron emission tomography tracers.

The non-specific binding of candidate positron emission tomography (PET) radiotracers causes resulting PET images to have poor contrast and is a key determinant for the success or failure of imaging drugs. Non-specific binding is thought to arise when radiotracers bind to cell membranes and moieties other than their intended target. Our previous preliminary work has proposed the use of the drug-lipid interaction energy descriptor to predict the level of non-specific binding in vivo using a limited set of ten well known PET radiotracers with kinetic modelling data taken from the literature.

Experimental exploration of the Mulliken-Hush relationship for intramolecular electron transfer reactions.

The Mulliken-Hush (M-H) relationship provides the critical link between optical and thermal electron transfer processes, and yet very little direct experimental support for its applicability has been provided. Dicyanovinylazaadamantane (DCVA) represents a simple two-state (neutral/charge-transfer) intramolecular electron transfer system that exhibits charge-transfer absorption and emission spectra that are readily measurable in solvents with a wide range of polarities. In this regard it represents an ideal model system for studying the factors that control both optical charge separation (absorption) and recombination (emission) processes in solution.