Unnatural Amino Acids Improve Affinity and Modulate Immunogenicity: Developing Peptides to Treat MHC Type II Autoimmune Disorders

Many autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and celiac disease (CD), arise from improper immune system recognition of self or benign peptides as threats. No autoimmune disease currently has a cure. Many treatments suppress the entire immune system to decrease symptom severity. The core molecular interaction underlying these diseases involves specific alleles of the human leukocyte antigen (HLA) receptor hosting the immunodominant peptides associated with the disease (i.e. myelin basic protein, Type II collagen, or α-gliadin) in their binding groove. Once bound, circulating T-cells can recognize the HLA-antigen complex and initiate the complex cascade that forms an adaptive immune response. This initial HLA-antigen interaction is a promising target for therapeutic intervention. Two general strategies have been pursued: altered peptide ligands (APLs) that attempt to recruit a different class of T-cell to induce an anti-inflammatory response to balance the pro-inflammatory response associated with the antigen; and HLA blockers (HLABs), peptides that, due to a much higher affinity for the HLA receptor, quantitatively displace the antigen, inhibiting the immune response. Both approaches would benefit from improved HLA-drug binding, but as the HLA receptors are highly promiscuous, the binding sites are not specific for any natural amino acid. Unnatural amino acids, either designed or screened through high-throughput assays, may provide a solution. This review summarizes the nascent field of using non-canonical residues to treat MS, RA and CD, focusing on the importance of specific molecular interactions, and provides some examples of the synthesis of these unnatural residues

Calcium-Ion Batteries: Identifying Ideal Electrolytes for Next-Generation Energy Storage Using Computational Analysis

Calcium ion batteries show promise as a high-density, next generation replacement for current lithium ion batteries. The precise chemical structure of the carbonate electrolyte solvent has a large impact on calcium battery efficacy. In this computational study, we have investigated the solvation behavior of calcium tetrafluoroborate in both neat carbonates and carbonate mixtures using combined molecular dynamics simulations and quantum mechanical calculations. Our results indicate that both neat ethyl methyl carbonate and a mixture of ethylene carbonate and diethyl carbonate show the highest free-energy of solvation for the Ca2+ ion, making them likely candidates for further focus. The cation’s interaction with the carbonyls of the coordinating solvents, rather than those with the tetrafluoroborate counterions, play the primary role in delocalizing the charge on Ca2+. Detailed calculations indicate that the HOMO-LUMO energy gap (Eg), electronic chemical potential (μ) and chemical hardness (η) of the calcium-carbonate complexes are directly proportional to the free energy of solvation of the complex. Comparison of these observed trends with our previous results from Li+, Na+ and Mg2+ ions show that this correlation is also observed in solvated magnesium ions, but not in lithium or sodium salts. This observation should assist in the rational design of next generation battery materials in the rational selection of additives, counterions, or electrolyte solvent

Not-So-Innocent Anions Determine the Mechanism of Cationic Alkylators

Alkylating reagents based on thioimidazolium ionic liquids were synthesized and the influence of the anion on the alkylation reaction mechanism explored in detail using both experimental and computational methods. Thioimidazolium cations transfer alkyl substituents to nucleophiles, however the reaction rate was highly dependent on anion identity, demonstrating that the anion is not innocent in the mechanism. Detailed analysis of the computationally-derived potential energy surfaces associated with possible mechanisms indicated that this dependence arises from a combination of anion induced electronic, steric and coordinating effects, with highly nucleophilic anions catalyzing a 2-step process while highly non-nucleophilic, delocalized anions favor a 1-step reaction. This work also confirms the presence of ion-pairs and aggregates in solution thus supporting anion-induced control over the reaction rate and mechanism. These findings provide new insight into an old reaction allowing for better design of cationic alkylators in synthesis, gene expression, polymer science, and protein chemistry applications

A DFT study of the adsorption of deep eutectic solvents onto graphene and defective graphene nanoflakes

The interaction of four deep choline chloride-derived eutectic solvents (DESs) with both graphene nanoflakes (GNF) and its defective double-vacancy and Stone–Wales forms (DV-GNF and SW-GNF), was evaluated using density functional theory (DFT). The presence of defects increases the adsorption energy of DESs, following the order DES∩DV-GNF \u3e DES∩SW-GNF \u3e DES∩GNF. Non-covalent interaction and energy decomposition analyses show that the interactions are noncovalent and dominated by dispersive forces. Furthermore, we find that the presence of aromatic moieties in the DESs increases the van der Waals interactions with the surfaces. These interactions decrease the HOMO-LUMO (Eg) energy gap of the surfaces and thus increase reactivity. Reactivity parameter calculations indicate that the chemical potential (μ) and chemical hardness (η) of the complexes follow the order DES∩GNF \u3e DES∩SW-GNF \u3e DES∩DV-GNF. This order is reversed for the global softness (S) and electrophilicity index (ω). Time-dependent DFT (TD-DFT) calculations predict that the adsorption of DESs onto DV-GNF and SW-GNF should red shift absorption, while the absorption spectrum of GNF surface remains unchanged upon DES adsorption. The biggest changes in the absorption spectra are observed upon adsorption of DESs on the DV-GNF surface due to the stronger affinity of the DESs for this surface

Not-So-Innocent Anions Determine the Mechanism of Cationic Alkylators

Alkylating reagents based on thioimidazolium ionic liquids were synthesized and the influence of the anion on the alkylation reaction mechanism explored in detail using both experimental and computational methods. Thioimidazolium cations transfer alkyl substituents to nucleophiles, however the reaction rate was highly dependent on anion identity, demonstrating that the anion is not innocent in the mechanism. Detailed analysis of the computationally-derived potential energy surfaces associated with possible mechanisms indicated that this dependence arises from a combination of anion induced electronic, steric and coordinating effects, with highly nucleophilic anions catalyzing a 2-step process while highly non-nucleophilic, delocalized anions favor a 1-step reaction. This work also confirms the presence of ion-pairs and aggregates in solution thus supporting anion-induced control over the reaction rate and mechanism. These findings provide new insight into an old reaction allowing for better design of cationic alkylators in synthesis, gene expression, polymer science, and protein chemistry applications

The effect of ionic liquid adsorption on the electronic and optical properties of fluorographene nanosheets

In the present study, we investigate the adsorption characteristics of six different ionic liquids (ILs) on a fully-fluorinated graphene (fluorographene, FG) surface using electronic structure studies and associated analysis methods. A systematic comparison of differences in IL binding energies (ΔEb) with fluorographene, graphene and hexagonal boron nitride surfaces indicates that fluorination strongly decreases the binding energy compared to the other two surfaces, hence resulting in the binding energetics: ΔEb (Graphene…IL) \u3e ΔEb (Hexagonal boron-nitride…IL) \u3e ΔEb (Fluorographene…IL). To probe the reasons for this difference, quantum theory of atoms in molecules (QTAIM) analysis and non-covalent interactions (NCI) analyses were carried out. Results indicate that the stability of complexes of FG surface with ILs (FG…IL) arises only due to the presence of the expected weak non-covalent intermolecular interactions. The calculation of charge transfers by employing the ChelpG method shows that the interaction of ILs with FG surface generally induces a negative charge on the FG surface. Furthermore, these interactions lead to a decrease of the HOMO-LUMO energy gap (Eg) of the FG surface, enhancing its electrical conductivity. In addition, a detailed analysis of the global molecular descriptors including the Fermi energy level (EFL), work function (WF), electronic chemical potential (μ), chemical hardness (η), global softness (S) and electrophilicity index (ω) was carried out for both the FG surface alone and the adsorbed complexes showing that there are small, but meaningful, differences in the reactivity of the surface depending on the nature of the IL. Finally, time-dependent DFT (TD-DFT) calculations of the optical properties of FG surface and FG…IL complexes reveal that the absorption spectrum of the FG surface undergoes a red shift following IL adsorption. This study demonstrates that FG provides a useful complementary tool to graphene and boron nitride materials, allowing for the fine-tuning of the optoelectronic properties of these monolayer materials. These results will assist in the development of these types of ILs for applications in optoelectronics

Reaction of Alkynyl- And Alkenyltrifluoroborates with Propargyldicobalt Cations: Alkynylation, Alkenylation, and Cyclopropanation Product Pathways

The Lewis acid-mediated Nicholas reactions of propargyl acetate–Co2(CO)6 complexes with a series of potassium alkynyltrifluoroborates and potassium alkenyltrifluoroborates are described. Alkynyltrifluoroborates directly alkynylate the intermediate propargyldicobalt cations. In contrast, alkenyltrifluoroborates proceed through one of the three modes of dominant reactivity: C-2-substituted alkenyltrifluorobrates directly alkenylate, predominantly with the retention of stereochemistry. C-1-substituted alkenyltrifluoroborates alkenylate at C-2. Potassium vinyltrifluoroborate incorporates a cyclopropane at the site propargyl to alkynedicobalt. Computational analysis of these systems explains the differential modes of reactivity of alkenyltrifluoroborates and outlines the probable mechanisms for the formation of each product

A theoretical first principles computational investigation into the potential of aluminum-doped boron nitride nanotubes for hydrogen storage

Hydrogen storage remains a largely unsolved problem facing the green energy revolution. One approach is physisorption on very high surface area materials incorporating metal atoms. Boron nitride nanotubes (BNNTs) are a promising material for this application as their behaviour is largely independent of the nanoscopic physical features providing a greater degree of tolerance in their synthesis. Aluminum doping has been shown to be a promising approach for carbon nanotubes but has been underexplored for BNNTs. Using first principles density functional theory, the energetics, electronics and structural impacts of aluminum adsorption to both zigzag and armchair polymorphs of BNNTs was investigated along with their potential capacity to adsorb hydrogen. The fine atomic structural and electronic details of these interactions is discussed. We predicted that in an ideal situation, highly aluminum-doped armchair and zigzag BNNTs could adsorb up to 9.4 and 8.6 weight percent hydrogen, well above the United States Department of Energy targets marking these as promising materials worthy of further study

Sharing the salt bowl: counterion identity drives N-alkyl resorcinarene affinity for pyrophosphate in water

N-Alkyl ammonium resorcinarene chloride receptors, NARX4, have been shown to act as high-sensitivity detectors of pyrophosphate (PPi), a biomarker of disease, in aqueous media through the chloride-to-PPi exchange [NAR(Cl)4 to NARPPi]. The nature of the anion of the macrocyclic NARX4 (X = Cl−, Br−, triflate OTf−) receptor greatly influences the PPi-affinity in aqueous media. The binding affinity for [NAR (Cl)4] is 3.61 × 105 M−1, while the NAR (Br)4 and NAR (OTf)4 show stronger binding of 5.30 × 105 M−1, and 6.10 × 105 M−1, respectively. The effects of upper rim ammonium cation, –N+H2R substituents (R = 3-hydroxypropyl, cyclohexyl, benzyl, or napththalen-1-ylmethyl), of the macrocyclic resorcinarene hosts have also been evaluated. The highest affinity was obtained using 3-hydroxypropyl groups due to the additional hydrogen bonds and the naphthyl upper-rim group that provides a larger hydrophobic surface area and favorable stacking interaction (i.e., π–π and CH–π). We note that two PPi molecules can bind to the more selective receptors through an additional interaction with the lower rim hydroxyls, making the resorcinarene a divalent binder. Comparing PPi with other phosphate anions (PO43−, AMP, ADP, and ATP) shows that the receptors are more selective for PPi due to the size and charge complementarity. Experimental (1H, 31P NMR, and isothermal titration calorimetry), and computational analyses support the reported trends for PPi selectivity even in highly competing aqueous media