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Concept: Conformational isomerism

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Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.

Concepts: Nervous system, Density functional theory, Neurotransmitter, Acetylcholine, Sarin, Deuterium, Acetylcholinesterase, Conformational isomerism

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Chlorogenic acid is a well-known antioxidant and has more isomers according to the difference in binding location and number of caffeic on quinic acid. In this study, we investigated and compared the profiles of antioxidant and DNA-protective activities of chlorogenic acid isomers including three caffeoylquinic acid isomers (3-O-caffeoylquinic acid, 3-CQA; 4-O-caffeoylquinic acid, 4-CQA; and 5-O- caffeoylquinic acid, 5-CQA) and three dicaffeoylquinic acid isomers (3,5-dicaffeoyl-quinic acid, ICAA; 3,4-dicaffeoylquinic acid, ICAB; and 4,5-dicaffeoyl-quinic acid, ICAC). The results showed that each of chlorogenic acid isomers studied exhibited antioxidant activities and DNA damage protective effects to various extents. On the whole, dicaffeoylquinic acids possessed better antioxidant activities, mostly because they have more hydroxyl groups than caffeoylquinic acids. Three caffeoylquinic acid isomers showed quite similar antioxidant activities, indicating that the position of esterification on the quinic moiety of caffeoylquinic acid had no effect on its antioxidant activities. Quite the contrary, a difference among dicaffeoylquinic acid isomers was observed, namely, ICAA and ICAB exhibited the same antioxidant activities, whereas ICAC had higher antioxidant activities than ICAA and ICAB in some assays, which implied that their antioxidant activities were probably influenced by the position of esterification on the quinic moiety. We speculated that this difference might be due to the fact that there may exist a steric hindrance effect in the ICAC. However, this assumption needs to be further confirmed.

Concepts: Alcohol, Functional group, Caffeic acid, Carboxylic acids, Conformational isomerism, Chlorogenic acid, Quinic acid, Cyclitols

28

With a view to development of novel sialidase inhibitors, mimetics of the natural inhibitor Neu5Ac2en have been prepared in which a phosphonate group replaces the sialic acid glycerol side chain. Different hex-4-en derivatives adopt half-chair conformations that place the glycosyl phosphonate in an equatorial position. For the α-L-threo-hex-4-en derivative this conformation is equivalent to that of Neu5Ac2en, and opposite to that seen for alkyl O-glycosides with the same overall stereochemistry.

Concepts: Tertiary structure, Stereochemistry, Calculus, Vector space, Derivative, Conformation, Conformational isomerism, Cyclohexane conformation

28

Nanobodies are single-domain antibodies found in camelids. These are the smallest naturally occurring binding domains and derive functionality via three hypervariable loops (H1, H2 and H3) which form the binding surface. They are excellent candidates for antibody engineering due to their favorable characteristics like small-size, high solubility, and stability. To rationally engineer antibodies with affinity for a specific target, one can tailor the hypervariable loops to obtain the desired binding surface. As a first step toward such a goal, we consider the design of loops with a desired conformation. In this study, we focus on the H1 loop of the anti-hCG llama nanobody which exhibits a non-canonical conformation. We aim to “tilt” the balance of the H1 loop conformation from a non-canonical conformation to a (humanized) type-1 canonical conformation by correlating the effect of selected mutations to the amino-acid sequence of the H1, H2 and proximal residues on the H1 loop conformation. We use all-atomistic, explicit-solvent, biased molecular dynamic simulations to simulate the wildtype and mutant loops in a pre-folded framework. We thus find mutants with increasing propensity to form a stable type-1 canonical conformation of the H1 loop. Free-energy landscapes reveal the existence of conformational isomers of the canonical conformation which may play a role in binding different antigenic surfaces. We also elucidate the approximate mechanism and kinetics of transitions between such conformational isomers by using a Markovian model. We find that a particular three-point mutant has the largest thermodynamic propensity to form the H1 type-1 canonical structure but also to exhibit transitions between conformational isomers, while a different, more rigid three-point mutant has the largest propensity to be kinetically trapped in such a canonical structure.

Concepts: Immune system, Antibody, Monoclonal antibodies, Tertiary structure, Conformation, Conformational isomerism, Isomer, Single domain antibody

28

Novel enantiopure pseudopeptide models containing a central -(beta-lactam)-(Aa)- scaffold characterized by the combined presence of an alpha-alkyl-alpha-amino-beta-lactam (i+1) residue and a alpha-substituted (i+2) amino acid have been readily synthesized from alpha-alkyl serines. The conformational analysis of such beta-lactam pseudopeptides conducted in CDCl3 and DMSOd6 solutions using 1D and 2D-NMR techniques revealed an equilibrium between beta-II turn and gamma-turn conformers, which was ultimately modulated by the relative configuration of the -(beta-lactam)-(Aa)- residues. Long range chiral effects on the alpha-lactam pseudopeptide conformers were also found when two (i) and (i+3) chiral residues were attached to the termini of a central -(beta-lactam)-(Aib)- segment. In such mimetics, heterochiral (i) and (i+3) residues reinforced a beta-II turn conformer, whereas homochiral corner residues stabilized an overlapped beta-II/ beta-I double turn motif. No beta-hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, beta-turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level and, finally, a conformation equilibrium model based on steric inter-residual interactions around the -(beta-lactam)-(i+2)- segment was proposed to account for the observed chiral effects.

Concepts: Amino acid, Stereochemistry, Steric effects, Conformational isomerism, Isomer, Folding, Cyclohexane conformation

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The concept of geometrical constraints and steric hindrance in reactions is implanted deeply in a chemist’s ‘chemical intuition’. However, until now a true three-dimensional view of these steric effects has not been realized experimentally for any chemical reaction in full. Here we report the complete three-dimensional characterization of the sterics of a benchmark polyatomic reaction by measuring the dependence of the product state-resolved angular distributions on the spatial alignment of the reactive bond in a crossed molecular beam experiment. The results prove the existence of two distinct microscopic reaction mechanisms. Detailed analysis reveals that the origin of the stereodynamics in the HCl(ν = 0) + CD(3)(0(0)) product channel can be captured by a textbook line-of-centres collision model. In contrast, a time-delay pathway, which includes a sharp switch from in-plane to out-of-plane scattering in the forwards direction, appears to be operative in forming the excited HCl(ν = 1) + CD(3)(0(0)) product pair.

Concepts: Chemical reaction, Molecule, Stereochemistry, Chemistry, Steric effects, Conformational isomerism, Random coil, Hyperconjugation

27

Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, , which selectively inhibited neutrophil elastase release induced by formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds , , , , and exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2˙(-)) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe () was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein.

Concepts: Monocyte, Neutrophil granulocyte, Elastase, Chronic granulomatous disease, Alpha 1-antitrypsin, Conformational isomerism, Formyl peptide receptor, Neutrophil elastase

27

The first Si-H-containing azasilaheterocycle, 1,3-dimethyl-3-silapiperidine 1, was synthesized and its molecular structure and conformational properties were studied by gas-phase electron diffraction (GED), low temperature NMR, IR and Raman spectroscopy and quantum chemical calculations. The compound exists as a mixture of two conformers possessing the chair conformation with the equatorial NMe group and differing by axial or equatorial position of the SiMe group. In the gas phase, the SiMeax conformer predominates (GED: ax/eq = 65(7):35(7) %), ΔG = 0.36(18) kcal/mol; IR: ax/eq = 62(5) : 38(5) %), ΔG = 0.16(7) kcal/mol). In solution, at 143 K the SiMeeq conformer predominates in the frozen equilibrium (NMR: ax/eq = 31.5(1.5) : 68.5(1.5) %), ΔG = -0.22(2) kcal/mol). Thermodynamic parameters of the ring inversion are determined (ΔG≠ = 8.9-9.0 kcal/mol, ΔH≠ = 9.6 kcal/mol, ΔS≠ = 2.1 eu). High-level quantum chemical calculations (MP2, G2, CCSD(T)) nicely reproduce the experimental geometry and the predominance of the axial conformer in the gas phase.

Concepts: Fundamental physics concepts, Stereochemistry, Chemistry, Chemical bond, Temperature, Chemical compound, Conformational isomerism, Cyclohexane conformation

26

The intramolecular Diels-Alder reactions of cycloalkenones and terminal dienes occur with high endo stereoselectivity, both thermally and under Lewis-acidic conditions. Through computations, we show that steric repulsion and tether conformation govern the selectivity of the reaction, and incorporation of either BF3 or α-halogenation increases the rate of cycloaddition. With a longer tether, isomerization from a terminal diene to the more stable internal diene results in a more facile cycloaddition.

Concepts: Stereochemistry, Gilbert N. Lewis, Acceleration, Steric effects, Diene, Conformational isomerism, Physical organic chemistry, Dienes

25

PEGylation in polymeric nanomedicine has gained substantial predominance in biomedical applications due to its resistance to protein absorption, which is critically important for a therapeutic delivery system in blood circulation. The shielding layer of PEGylation, however, creates significant steric hindrance that negatively impacts cellular uptake and intracellular distribution at the target site. This unexpected effect compromises the biological efficacy of the encapsulated payload. To address this issue, one of the key strategies is to tether the disulfide bond to PEG for constructing a disulfide-bridged cleavable PEGylation. The reversible disulfide bond can be cleaved to enable selective PEG detachment. This article provides an overview on the strategy, method and progress of PEGylation nanosystem with the cleavable disulfide bond.

Concepts: Protein, Molecular biology, Blood, Heart, Disulfide bond, Steric effects, Conformational isomerism, Random coil