Multiscale Measurements of Greenhouse Gas Emissions at U.S. Natural Gas Liquefaction Terminals.

Addressing methane emissions across the liquefied natural gas (LNG) supply chain is key to reducing climate impacts of LNG. Actions to address methane emissions have emphasized the importance of the use of measurement-informed emissions inventories given the systematic underestimation in official greenhouse gas (GHG) emission inventories. Despite significant progress in field measurements of GHG emissions across the natural gas supply chain, no detailed measurements at US liquefaction terminals are publicly available.

The maximal and current accuracy of rigorous protein-ligand binding free energy calculations.

Computational techniques can speed up the identification of hits and accelerate the development of candidate molecules for drug discovery. Among techniques for predicting relative binding affinities, the most consistently accurate is free energy perturbation (FEP), a class of rigorous physics-based methods. However, uncertainty remains about how accurate FEP is and can ever be.

Informing Methane Emissions Inventories Using Facility Aerial Measurements at Midstream Natural Gas Facilities.

Increased interest in greenhouse gas (GHG) emissions, including recent legislative action and voluntary programs, has increased attention on quantifying and ultimately reducing methane emissions from the natural gas supply chain. While inventories used for public or corporate GHG policies have traditionally utilized bottom-up (BU) methods to estimate emissions, the validity of such inventories has been questioned. Therefore, there is attention on utilizing full-facility measurements using airborne, satellite, or drone (top-down (TD)) techniques to inform, improve, or validate inventories.

OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space.

We report on the development and validation of the OPLS4 force field. OPLS4 builds upon our previous work with OPLS3e to improve model accuracy on challenging regimes of drug-like chemical space that includes molecular ions and sulfur-containing moieties. A novel parametrization strategy for charged species, which can be extended to other systems, is introduced.

Directed and Metalation of Naphthalene 1,8-Diamide: Complementing SAr Reactivity for the Synthesis of Substituted Naphthalenes.

Mono- and dianion species of 1,8-naphthalene diamide were generated under -BuLi/TMEDA conditions and trapped with a variety of electrophiles to give 2- and 2,7- substituted products and . Using Suzuki-Miyaura cross-coupling, mono- and di-iodinated products were converted into the corresponding 2-aryl () and 2,7-diaryl () products, respectively. The amide-amide rotation barrier of was established by VT NMR, and the structure of fluorenone structure , obtained by metalation, was secured.

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo.

The prediction of protein-ligand binding affinities using free energy perturbation (FEP) is becoming increasingly routine in structure-based drug discovery. Most FEP packages use molecular dynamics (MD) to sample the configurations of proteins and ligands, as MD is well-suited to capturing coupled motion. However, MD can be prohibitively inefficient at sampling water molecules that are buried within binding sites, which has severely limited the domain of applicability of FEP and its prospective usage in drug discovery.

An intra-aortic guide wire: what "knot" to do.

We report a rare complication of central venous catheter placement in a 5-month-old baby.

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2.

Ligand Binding Free Energies with Adaptive Water Networks: Two-Dimensional Grand Canonical Alchemical Perturbations.

Computational methods to calculate ligand binding affinities are increasing in popularity, due to improvements in simulation algorithms, computational resources, and easy-to-use software. However, issues can arise in relative ligand binding free energy simulations if the ligands considered have different active site water networks, as simulations are typically performed with a predetermined number of water molecules (fixed N ensembles) in preassigned locations. If an alchemical perturbation is attempted where the change should result in a different active site water network, the water molecules may not be able to adapt appropriately within the time scales of the simulations-particularly if the active site is occluded.

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo.

Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement.

Biomolecular Simulations under Realistic Macroscopic Salt Conditions.

Biomolecular simulations are typically performed in an aqueous environment where the number of ions remains fixed for the duration of the simulation, generally with either a minimally neutralizing ion environment or a number of salt pairs intended to match the macroscopic salt concentration. In contrast, real biomolecules experience local ion environments where the salt concentration is dynamic and may differ from bulk. The degree of salt concentration variability and average deviation from the macroscopic concentration remains, as yet, unknown.

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes via Nonequilibrium Candidate Monte Carlo.

Accurately predicting protein-ligand binding affinities and binding modes is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant.

Replica-Exchange and Standard State Binding Free Energies with Grand Canonical Monte Carlo.

The ability of grand canonical Monte Carlo (GCMC) to create and annihilate molecules in a given region greatly aids the identification of water sites and water binding free energies in protein cavities. However, acceptance rates without the application of biased moves can be low, resulting in large variations in the observed water occupancies. Here, we show that replica-exchange of the chemical potential significantly reduces the variance of the GCMC data.

Nerve growth factor inhibitor with novel-binding domain demonstrates nanomolar efficacy in both cell-based and cell-free assay systems.

Nerve growth factor (NGF), a member of the neurotrophin family, is known to regulate the development and survival of a select population of neurons through the binding and activation of the TrkA receptor. Elevated levels of NGF have been associated with painful pathologies such as diabetic neuropathy and fibromyalgia. However, completely inhibiting the NGF signal could hold significant side effects, such as those observed in a genetic condition called congenital insensitivity to pain and anhidrosis (CIPA).

Mitochondrial genome evolution in Alismatales: Size reduction and extensive loss of ribosomal protein genes.

The order Alismatales is a hotspot for evolution of plant mitochondrial genomes characterized by remarkable differences in genome size, substitution rates, RNA editing, retrotranscription, gene loss and intron loss. Here we have sequenced the complete mitogenomes of Zostera marina and Stratiotes aloides, which together with previously sequenced mitogenomes from Butomus and Spirodela, provide new evolutionary evidence of genome size reduction, gene loss and transfer to the nucleus. The Zostera mitogenome includes a large portion of DNA transferred from the plastome, yet it is the smallest known mitogenome from a non-parasitic plant.

Waterdock 2.0: Water placement prediction for Holo-structures with a pymol plugin.

Water is often found to mediate interactions between a ligand and a protein. It can play a significant role in orientating the ligand within a binding pocket and contribute to the free energy of binding. It would thus be extremely useful to be able to accurately predict the position and orientation of water molecules within a binding pocket.

Localized Retroprocessing as a Model of Intron Loss in the Plant Mitochondrial Genome.

Loss of introns in plant mitochondrial genes is commonly explained by retroprocessing. Under this model, an mRNA is reverse transcribed and integrated back into the genome, simultaneously affecting the contents of introns and edited sites. To evaluate the extent to which retroprocessing explains intron loss, we analyzed patterns of intron content and predicted RNA editing for whole mitochondrial genomes of 30 species in the monocot order Alismatales.

Plastid phylogenomics and molecular evolution of Alismatales.

Past phylogenetic studies of the monocot order Alismatales left several higher-order relationships unresolved. We addressed these uncertainties using a nearly complete genus-level sampling of whole plastid genomes (gene sets representing 83 protein-coding and ribosomal genes) from members of the core alismatid families, Tofieldiaceae and additional taxa (Araceae and other angiosperms). Parsimony and likelihood analyses inferred generally highly congruent phylogenetic relationships within the order, and several alternative likelihood partitioning schemes had little impact on patterns of clade support.

Phylogeny of the Alismatales (Monocotyledons) and the relationship of Acorus (Acorales?).

A phylogenetic analysis of the early branching lineages of the monocotyledons is performed using data from two plastid genes (rbcL and matK), five mitochondrial genes (atp1, ccmB, cob, mttB and nad5) and morphology. The complete matrix includes 93 terminals representing Acorus, the 14 families currently recognized within Alismatales, and numerous lineages of monocotyledons and other angiosperms. Total evidence analysis results in an almost completely resolved strict consensus tree, but all data partitions, genomic as well as morphological, are incongruent.

Using surface plasmon resonance spectroscopy to characterize the inhibition of NGF-p75(NTR) and proNGF-p75(NTR) interactions by small molecule inhibitors.

Nerve growth factor (NGF), a member of the neurotrophin family, acts to influence the survival and differentiation of neurons in both the central and peripheral nervous systems via its binding to the p75(NTR) and TrkA receptors. Its precursor, proNGF, has been shown to be the dominant form of NGF in the central nervous system, suggesting a biological function beyond its role as a precursor. Like NGF, proNGF is known to bind the p75(NTR) receptor.

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo.

Water molecules play integral roles in the formation of many protein-ligand complexes, and recent computational efforts have been focused on predicting the thermodynamic properties of individual waters and how they may be exploited in rational drug design. However, when water molecules form highly coupled hydrogen-bonding networks, there is, as yet, no method that can rigorously calculate the free energy to bind the entire network or assess the degree of cooperativity between waters. In this work, we report theoretical and methodological developments to the grand canonical Monte Carlo simulation technique.

Characterizing nerve growth factor-p75(NTR) interactions and small molecule inhibition using surface plasmon resonance spectroscopy.

Nerve growth factor (NGF) is critical for the proliferation, differentiation, and survival of neurons through its binding to the p75(NTR) and TrkA receptors. Dysregulation of NGF has been implicated in several pathologies, including neurodegeneration (i.e.

A Surface Plasmon Resonance Spectroscopy Method for Characterizing Small-Molecule Binding to Nerve Growth Factor.

Small-molecule inhibitors have been previously investigated to identify possible therapeutics for the treatment of chronic pain. In the present study, known nerve growth factor (NGF) inhibitors identified by (125)I-NGF binding were characterized using affinity and binding evaluations by surface plasmon resonance (SPR) spectroscopy. A novel strategy for characterizing NGF inhibitors was used to determine the binding affinity (KD) and saturation ability of each compound with immobilized NGF.

Microalgae cultivation in a novel top-lit gas-lift open bioreactor.

This work investigated a top-lit open microalgae bioreactor that uses a gas-lift system to enable deeper production depths, thereby significantly reducing the footprint. Growth of Scenedesmus sp. in a one-meter deep system by sparged with 6% CO2-enhanced air was evaluated.