Dudleydelaney2018

A high population of disorderness was observed in the IDP-specific force field for the IDP ensemble with a fraction of β sheets for β-amyloids. CHARMM22* performs better for many observables; however, it still has a preference toward the helicity for short peptides. The results of β-amyloid 42 starting from two different initial structures (Aβ421Z0Q and Aβ42model) were also compared with DSSP and NMR data. The results obtained with IDP-specific force fields within 2 μs simulation time are similar, even though starting from different structures. The current force fields perform equally well for folded proteins. The results of currently developed or modified force fields for IDPs are capable of enlightening the overall performance of the force field for disordered as well as folded proteins, thereby contributing to force field development.Albeit achieving the X-ray diffraction structure of dimeric photosystem II core complexes (dPSIIcc) at the atomic resolution, the nature of the detergent belt surrounding dPSIIcc remains ambiguous. Therefore, the solution structure of the whole detergent-protein complex of dPSIIcc of Thermosynechococcus elongatus (T. elongatus) solubilized in n-dodecyl-ß-d-maltoside (ßDM) was investigated by a combination of small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) with contrast variation. First, the structure of dPSIIcc was studied separately in SANS experiments using a contrast of 5% D2O. Guinier analysis reveals that the dPSIIcc solution is virtually free of aggregation in the studied concentration range of 2-10 mg/mL dPSIIcc, and characterized by a radius of gyration of 62 Å. A structure reconstitution shows that dPSIIcc in buffer solution widely retains the crystal structure reported by X-ray free electron laser studies at room temperature with a slight expansion of the entire proteinarger unbound detergent aggregates in solution prior to crystallization may have a significant effect on the crystal formation or quality of the ßDM-dPSIIcc.Chronic hepatitis C (CHC) is a major liver disease caused by the hepatitis C virus. The current standard of care for CHC can achieve cure rates above 95%; however, the drugs in current use are administered for a period of 8-16 weeks. A combination of safe and effective drugs with a shorter treatment period is highly desirable. We report synthesis and biological evaluation of a series of 2',3'- and 2',4'-substituted guanosine nucleotide analogues. Their triphosphates exhibited potent inhibition of the HCV NS5B polymerase with IC50 as low as 0.13 μM. In the HCV replicon assay, the phosphoramidate prodrugs of these analogues demonstrated excellent activity with EC50 values as low as 5 nM. Tecovirimat in vivo A lead compound AL-611 showed high levels of the nucleoside 5'-triphosphate in vitro in primary human hepatocytes and in vivo in dog liver following oral administration.Hydration of ions plays a crucial role in interionic interactions and associated processes in aqueous media, but selective probing of the hydration shell water is nontrivial. Here, we introduce Raman difference with simultaneous curve fitting (RD-SCF) analysis to extract the OH-stretch spectrum of hydration shell water, not only for the fully hydrated ions (Mg2+, La3+, and Cl-) but also for the ion pairs. RD-SCF analyses of diluted MgCl2 (0.18 M) and LaCl3 (0.12 M) solutions relative to aqueous NaCl of equivalent Cl- concentrations provide the OH-stretch spectra of water in the hydration shells of fully hydrated Mg2+ and La3+ cations relative to that of Na+. Integrated intensities of the hydration shell spectra of Mg2+ and La3+ ions increase linearly with the salt concentration (up to 2.0 M MgCl2 and 1.3 M LaCl3), which suggests no contact ion pair (CIP) formation in the MgCl2 and LaCl3 solutions. Nevertheless, the band shapes of the cation hydration shell spectra show a growing signature of Cl--associated water with the rising salt concentration, which is a manifestation of the formation of a solvent-shared ion pair (SSIP). The OH-stretch spectrum of the shared/intervening water in the SSIP, retrieved by second-round RD-SCF analysis (2RD-SCF), shows that the average H-bonding of the shared water is weaker than that of the hydration water of the fully hydrated cation (Mg2+ or La3+) but stronger than that of the anion (Cl-). The shared water displays an overall second-order dependence on the concentration of the interacting ions, unveiling 11 stoichiometry of the SSIP formed between Mg2+ and Cl- as well as La3+ and Cl-.Aberrant protein folding leading to the formation of characteristic cross-β-sheet-rich amyloid structures is well known for its association with a variety of debilitating human diseases. Often, depending upon amino acid composition, only a small segment of a large protein participates in amyloid formation and is in fact capable of self-assembling into amyloid, independent of the rest of the protein. Therefore, such peptide fragments serve as useful model systems for understanding the process of amyloid formation. An important factor that has often been overlooked while using peptides to mimic full-length protein is the charge on the termini of these peptides. Here, we show the influence of terminal charges on the aggregation of an amyloidogenic peptide from microtubule-associated protein Tau, implicated in Alzheimer's disease and tauopathies. We found that modification of terminal charges by capping the peptide at one or both of the termini drastically modulates the fibrillation of the hexapeptide sequence paired helical filament 6 (PHF6) from repeat 3 of Tau, both with and without heparin. Without heparin, the PHF6 peptide capped at both termini and PHF6 capped only at the N-terminus self-assembled to form amyloid fibrils. With heparin, all capping variants of PHF6, except for PHF6 with both termini free, formed typical amyloid fibrils. However, the rate and extent of aggregation both with and without heparin as well as the morphology of aggregates were found to be highly dependent on the terminal charges. Our molecular dynamics simulations on PHF6 capping variants corroborated our experiments and provided critical insights into the mechanism of PHF6 self-assembly. Overall, our results emphasize the importance of terminal modifications in fibrillation of small peptide fragments and provide significant insights into the aggregation of a small Tau fragment, which is considered essential for Tau filament assembly.Furans are promising second generation biofuels with comparable energy densities to conventional fossil fuels. Combustion of furans is initiated and controlled to a large part by reactions with OH radicals, the kinetics of which are critical to understand the processes occurring under conditions relevant to low-temperature combustion. The reactions of OH radicals with furan (OH + F, R1), 2-methyl furan (OH + 2-MF, R2), and 2,5-dimethyl furan (OH + 2,5-DMF, R3) have been studied in this work over the temperature range 294-668 K at pressures between 5 mbar and 10 bar using laser flash photolysis coupled with laser-induced fluorescence (LIF) spectroscopy to generate and monitor OH radicals under pseudo-first-order conditions. Measurements at p ≤ 200 mbar were made in N2, using H2O2 or (CH3)3COOH radical precursors, while those at p ≥ 2 bar were made in He, using HNO3 as the radical precursor. The kinetics of reactions R1-R3 were observed to display a negative dependence on temperature over the range investigated, indicating the dominance of addition reactions under such conditions, with no significant dependence on pressure observed. Master equation calculations are in good agreement with the observed kinetics, and a combined parametrization of addition channels and abstraction channels for R1-R3 is provided on the basis of this work and previous shock tube measurements at higher temperatures. This work significantly extends the temperature range previously investigated for R1 and represents the first temperature-dependent measurements of R2 and R3 at temperatures relevant for atmospheric chemistry and low-temperature combustion.In this work, we present a set of virial relations for many electron systems coupled to both classical and quantum fields, described by the Pauli-Fierz Hamiltonian in dipole approximation and using length gauge. Currently, there is growing interest in solutions of this Hamiltonian because of its relevance for describing molecular systems strongly coupled to photonic modes in cavities and in the possible modification of chemical properties of such systems compared to the ones in free space. The relevance of such virial relations is demonstrated by showing a connection to mass renormalization and by providing an exact way to obtain total energies from potentials in the framework of quantum electrodynamical density functional theory.The spreading of malaria parasites, Plasmodium falciparum, with resistance to all known drugs calls for novel classes of inhibitors with new modes of action. Recently, we discovered and validated the plasmodial l-lactate transporter, PfFNT, as a novel antimalarial drug target. However, treatment of parasites with a screening hit from the malaria box compound collection, MMV007839, gave rise to a PfFNT Gly107Ser resistance mutation decreasing inhibitor affinity by 2 orders of magnitude. Here, we show that newly introduced nitrogen atoms into the inhibitor scaffold can act as hydrogen bond acceptor sites to the serine hydroxyl. The gain in affinity led to almost equal inhibition of wildtype PfFNT and the Gly107Ser mutation. The most potent inhibitor of this work, BH267.meta, killed cultured P. falciparum parasites with nanomolar efficacy and did not give rise to new resistance formation in vitro. Its deduced pharmacokinetic properties appear suitable for further drug development.We present an approach combining a representation of a multivariate function using subdimensional functions with machine learning based representation of component functions Random sampling high dimensional model representation Gaussian process regression (RS-HDMR-GPR). The use of Gaussian process regressions to represent component functions allows nonparametric (unbiased) representation and the possibility to work only with functions of desired dimensionality, obviating the need to build an expansion over orders of coupling. All component functions are determined from a single set of samples. The method is tested by fitting six- and 15-dimensional potential energy surfaces (PES) of polyatomic molecules as well as by computing vibrational spectra for a four-atomic molecule.The trichophycin family of compounds are chlorinated polyketides first discovered from environmental collections of a bloom-forming Trichodesmium sp. cyanobacterium. In an effort to fully capture the chemical space of this group of metabolites, the utilization of MS/MS-based molecular networking of a Trichodesmium thiebautii extract revealed a metabolome replete with halogenated compounds. Subsequent MS-guided isolation resulted in the characterization of isotrichophycin C and trichophycins G-I (1-4). These new metabolites had intriguing structural variations from those trichophycins previously characterized, which allowed for a comparative study to examine structural features that are associated with toxicity to murine neuroblastoma cells. Additionally, we propose the absolute configuration of the previously characterized trichophycin A (5). Overall, the metabolome of the Trichodesmium bloom is hallmarked by an unprecedented amount of chlorinated molecules, many of which remain to be structurally characterized.