Kristoffersenpetterson7231

The thermal stability of the superoxide dismutase 1 protein in a crowded solution is investigated by performing enhanced sampling molecular simulations. By complementing thermal unfolding experiments done close to physiological conditions (200 mg/mL), we provide evidence that the presence of the protein crowder bovine serum albumin in different packing states has only a minor, and essentially destabilizing, effect. The finding that quinary interactions counteract the pure stabilization contribution stemming from excluded volume is rationalized here by exploring the SOD1 unfolding mechanism in microscopic detail. In agreement with recent experiments, we unveil the importance of intermediate unfolded states as well as the correlation between protein conformations and local packing with the crowders. Streptozocin This link helps us to elucidate why certain SOD1 mutations involved in the ALS disease reverse the stability effect of the intracellular environment.Sessile droplet evaporation is widely encountered in nature, and it has numerous applications in industrial and scientific communities; therefore, the accurate prediction of droplet evaporation has great significance in practical applications. In this paper, for the first time, a comprehensive theoretical model is built up for diffusion-controlled heat and mass transfer for sessile droplet evaporation on a curved substrate in toroidal coordinates. The evaporative mass transfer is coupled with the heat transfer across the gas-liquid droplet interface, as well as the heat transfer across the solid-liquid interface of the curved substrate. The effects of interfacial cooling and thermal conductivity of the droplet and substrate as well as their initial shapes on the droplet evaporation are provided in details. It is found that the evaporative flux usually increases sharply near the droplet edge due to the short distance for heat conduction from the substrate to the droplet; however, it can be reversed from sharp increasing to decreasing at a low thermal conductivity ratio kR 30°. The interfacial evaporative cooling effect can always suppress the droplet evaporation. The lifetime of evaporative droplet can be prolonged with the decreasing thermal conductivity ratio, increasing evaporative cooling number, and increasing initial droplet contact angle or tangential angle of a curved substrate. These findings may be of great significance in the applications of droplet evaporation on the curved substrate.Physical confinement of polymers not only affects their structure but also modifies their effective interaction profiles. In this article, we investigate the nature of graphene-adsorbed poly(amidoamine) (PAMAM) dendrimers' interactions using fully atomistic molecular dynamics simulations. Using the umbrella sampling technique, we calculate the potential of mean force (PMF) profiles for the interaction between two graphene-adsorbed PAMAM dendrimers of generations 3 and 4 as a function of their protonation levels. We find that the attractive PMF profile observed for the interaction between two nonprotonated (high pH) PAMAM dendrimers in bulk becomes repulsive upon adsorption. Also, the repulsive interdendrimer interactions known in bulk for the protonated dendrimers become enhanced for the adsorbed case. We further explain these weakened interactions by explicitly showing that the dendrimer-graphene interaction is an order of magnitude larger than the dendrimer-dendrimer bulk interaction. Using the force integration method, we obtain the contributions from various subinteractions present in the system, that is, dendrimer-water, dendrimer-ions, dendrimer-graphene, and dendrimer-dendrimer to the total PMF. From these contributions, we conclude that the reduced dendrimer-dendrimer interactions in the adsorbed case, as compared to those in bulk, lead to the enhanced repulsive effective interdendrimer interactions. Our PMF profiles fit well with the sum of exponential and Gaussian functions, proposed in the bulk interdendrimer interaction study. We hope the current results provide the microscopic origin of how adsorption weakens the interpolymer interactions in general.Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. link2 Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.Biology takes place in crowded, heterogeneous environments, and it is therefore essential to account for crowding effects in our understanding of biophysical processes at the molecular level. Comparable to the cytosol, proteins occupy approximately 30% of the plasma membrane surface; thus, crowding should have an effect on the local structure and dynamics at the lipid-water interface. Using a combination of ultrafast two-dimensional infrared spectroscopy and molecular dynamics simulations, we quantify the effects of membrane peptide concentration on the picosecond interfacial H-bond dynamics. The measurements reveal a nonmonotonic dependence of water orientation and dynamics as a function of transmembrane peptidelipid ratio. We observe three dynamical regimes a "pure lipid-like" regime at low peptide concentrations, a bulk-like region at intermediate peptide concentrations where dynamics are faster by ∼20% compared to those of the pure lipid bilayer, and a crowded regime where high peptide concentrations slow dynamics by ∼50%.A density functional theory study of the mechanism of the Borono-Mannich reaction using benzylamine and piperidine as representative examples of primary and secondary amines with pinacol allenylboronate is presented. The study shows that both reactions progress through coordination between the boron and the phenolic oxygen. Ring size strain and hydrogen bond activation appear to determine the observed divergent regioselectivity. In the case of benzylamine, the eight-membered ring transition structure that leads to the propargylamine exhibits a hydrogen bond between the hydrogen attached to the nitrogen and the phenolic oxygen (γ-attack), whereas for piperidine a hydrogen bond between the hydrogen on the imine carbon and one of the oxygens of the pinacol group was observed in the six-membered ring transition structure toward the allenylamine (α-attack).Abstract) Theoretical calculations were performed to investigate the interplay between sigma holes, anion-HC and cation-π interactions in the complexes of dibromo [2-2] paracyclophane (DBr[2-2]PCP) with alkali (Li+, Na+, K+ ), alkaline earth metal cations (Be++, Mg++, Ca++) and halogen anions (F-, Cl- and Br-) using the wavefunction (MP2) and density functional theory (M06-2X and B3LYP) methods with the 6-311++G(d, p) basis set. link3 The study reveals that DBr[2-2]PCP behaves as amphoteric molecule with a predominance of basic character. It prefers to interact with hard cations and hard anions such as Be++ and F- through cation-π and anion…HC interactions, respectively. Substitution of Br by F and Cl atoms in DBr[2-2]PCP does not increase the stabilities of DX[2-2]PCP-halogen anion complexes (X = F, Cl, Br). The anion-HC interactions in DBr[2-2]PCP complexes were found to be ~10 kcal/mol stronger (at B3LYP, ~15 kcal/mol at M06-2X and 7 kcal/mol at MP2) than the sigma holes.Photoredox catalysis using proton-coupled electron transfer (PCET) has emerged as a powerful method for bond transformations. We previously employed traditional chemical oxidants to achieve multiple-site concerted proton-electron transfer (MS-CPET) activation of a C-H bond in a proof-of-concept fluorenyl-benzoate substrate. As described here, photoredox oxidation of the fluorenyl-benzoate follows the same rate constant vs driving force trend determined for thermal MS-CPET. Analogous photoredox catalysis enables C-H activation and H/D exchange in a number of additional substrates with favorably positioned bases. Mechanistic studies support our hypothesis that MS-CPET is a viable pathway for bond activation for substrates in which the C-H bond is weak, while stepwise carboxylate oxidation and hydrogen atom transfer likely predominate for stronger C-H bonds.Challenges to the de novo synthesis of bacteriochlorophyll a (BChl a), the chief pigment for anoxygenic bacterial photosynthesis, include creating the macrocycle along with the trans-dialkyl substituents in both pyrroline rings (B and D). A known route to a model bacteriochlorophyll with a gem-dimethyl group in each pyrroline ring has been probed for utility in the synthesis of BChl a by preparation of a hybrid macrocycle (BC-1), which contains a trans-dialkyl group in ring D and a gem-dimethyl group in ring B. Stereochemical definition began with the synthesis of (2S,3S)-2-ethyl-3-methylpent-4-ynoic acid, a precursor to the trans-dialkyl-substituted AD dihydrodipyrrin. Knoevenagel condensation of the latter and a gem-dimethyl, β-ketoester-substituted BC dihydrodipyrrin afforded the enone (E, 70%; Z, 3%); subsequent double-ring cyclization of the E-enone (via Nazarov, electrophilic aromatic substitution, and elimination reactions) gave BC-1 (53% yield) along with a trace of chlorin byproduct (1.4% relative to BC-1 upon fluorescence assay). BC-1 exhibited the desired trans-dialkyl stereochemistry in ring D and was obtained as a 71 mixture of (expected) epimers owing to the configuration of the 132-carbomethoxy substituent. The strategy wherein trans-dialkyl substituents are installed very early and carried through to completion, as validated herein, potentially opens a synthetic path to native photosynthetic pigments.Few chemical methods exist for the covalent conjugation of two proteins. We report the preparation of site-specific protein-protein conjugates that arise from the sequential cross-coupling of cysteine residues on two different proteins. The method involves the synthesis of stable palladium-protein oxidative addition complexes (Pd-protein OACs), a process that converts nucleophilic cysteine residues into an electrophilic S-aryl-Pd-X unit by taking advantage of an intramolecular oxidative addition strategy. This process is demonstrated on proteins up to 83 kDa in size and can be conveniently carried out in water and open to air. The resulting Pd-protein OACs can cross-couple with other thiol-containing proteins to arrive at homogeneous protein-protein bioconjugates.Atomic-scale defects in two-dimensional transition metal dichalcogenides (TMDs) often dominate their physical and chemical properties. Introducing defects in a controllable manner can tailor properties of TMDs. For example, chalcogen atom defects in TMDs were reported to trigger phase transition, induce ferromagnetism, and drive superconductivity. However, reported strategies to induce chalcogen atom defects including postgrowth annealing, laser irradiation, or plasma usually require high temperature (such as 500 °C) or cause unwanted structural damage. Here, we demonstrate low-temperature (60 °C) partial surface oxidation in 2D PdSe2 with low disorder and good stability. The combination of scanning tunneling microscopy, X-ray photoelectron spectroscopy, and density functional theory calculations provide evidence of atomic-scale partial oxidation with both atomic resolution and chemical sensitivity. We also experimentally demonstrate that this controllable oxygen incorporation effectively tailors the electronic, optoelectronic, and catalytic activity of PdSe2.