Network Of Weak Interactions Research Articles

The Unconventional Noncovalent Interactions Control: Crystallographic and Theoretical Analyses of the Crystalline Structure of 1,1′‐(1‐Chloro‐4‐methoxyphenyl)dibenzene as a Case Study

AbstractUnconventional noncovalent interactions are ubiquitous in molecular crystals, supramolecular systems, and biomolecules, but their significance has often been overshadowed by stronger intermolecular interactions such as hydrogen bonding and π‐stacking. This study aims to emphasize the significance of nonclassical noncovalent interactions in crystal packing. The crystal structure of 1,1′‐(1‐chloro‐4‐methoxyphenyl)dibenzene was reported as a representative case. A network of weak interactions governs the arrangement of the molecules within the crystal, encompassing C−H⋅⋅⋅X hydrogen bonding (where X=O, Cl, or π), weak Cl⋅⋅⋅Cl symmetrical bonding (classified as Type I halogen–halogen bonding), and C−H…H−C homopolar dihydrogen contacts (dH…H=2.348 Å). The nature, energetics, and cooperativity of these interactions were evaluated using computational calculations based on dispersion‐corrected density functional theory (DFT/wB97X‐D/aug‐cc‐pVTZ). Our findings contribute to a comprehensive understanding of unconventional noncovalent interactions and their role in crystal packing. The methods and concepts employed are likely to be applicable to other molecular systems in biology, chemistry, and materials science.

Regiocontrolled Rh(III)-catalyzed C[sbnd]C coupling/C[sbnd]N cyclization mediated by distinctive 1,2-migratory insertion of gem‑difluoromethylene allenes: Reaction development and mechanistic insight

By developing gem‑difluoromethylene allenes as viable partners, regiocontrolled Rh(III)-catalyzed redox-neutral CC coupling/CN cyclization has been realized to build the pyridin-2(1H)-one motifs with the embedment of a Z-configured monofluoroalkene functionality, in which either (hetero)aromatic or vinylic amides were found to be compatible. Integrated experimental and computational mechanistic studies revealed that a tandem regioselective allene 1,2-insertion/β-H elimination/hydrogen transfer/oxidative addition/cyclization/cis-β-F elimination involving an unconventional Rh(III)-Rh(I)-Rh(III) catalytic cycle accounts for the established transformation. Through further FMO analysis and IGMH maps, a non-covalent weak interaction network between the gem‑difluoromethylene part and the OPiv moiety was rationally defined for the unconventional and specific regioselectivity control.

Uncovering the Networks of Topological Neighborhoods in \u03b2-Strand and Amyloid \u03b2-Sheet Structures

Although multiple hydrophobic, aromatic π–π, and electrostatic interactions are proposed to be involved in amyloid fibril formation, the precise interactions within amyloid structures remain poorly understood. Here, we carried out detailed quantum theory of atoms-in-molecules (QTAIM) analysis to examine the hydrophobic core of amyloid parallel and antiparallel β-sheet structures, and found the presence of multiple inter-strand and intra-strand topological neighborhoods, represented by networks of through-space bond paths. Similar bond paths from side chain to side chain and from side chain to main chain were found in a single β-strand and in di- and tripeptides. Some of these bond-path networks were enhanced upon β-sheet formation. Overall, our results indicate that the cumulative network of weak interactions, including various types of hydrogen bonding (X-H—Y; X, Y = H, C, O, N, S), as well as non-H-non-H bond paths, is characteristic of amyloid β-sheet structure. The present study postulated that the presence of multiple through-space bond-paths, which are local and directional, can coincide with the attractive proximity effect in forming peptide assemblies. This is consistent with a new view of the van der Waals (vdW) interactions, one of the origins of hydrophobic interaction, which is updating to be a directional intermolecular force.

Altered dynamics may drift pathological fibrillization in membraneless organelles

Protein phase transition can generate non-membrane bound cellular compartments, which can convert from liquid-like to solid-like states. While the molecular driving forces of phase separation have been largely understood, much less is known about the mechanisms of material-state conversion. We apply a recently developed algorithm to describe the weak interaction network of multivalent motifs, and simulate the effect of pathological mutations. We demonstrate that linker dynamics is critical to the material-state of biomolecular condensates. We show that linker flexibility/mobility is a major regulator of the weak, heterogeneous meshwork of multivalent motifs, which promotes phase transition and maintains a liquid-like state. Decreasing linker dynamics increases the propensity of amyloid-like fragments via hampering the motif-exchange and reorganization of the weak interaction network. In contrast, increasing linker mobility may compensate rigidifying mutations, suggesting that the meshwork of weak, variable interactions may provide a rescue mechanism from aggregation. Motif affinity, on the other hand, has a moderate impact on fibrillization. Here we demonstrate that the fuzzy framework provides an efficient approach to handle the intricate organization of membraneless organelles, and could also be applicable to screen for pathological effects of mutations.

Structure and catalytic mechanistic insight into Enterobacter aerogenes acetolactate decarboxylase

α-Acetolactate decarboxylase (ALDC) catalyses α-acetolactate into acetoin (3-hydroxy-2-butanone, AC) and is considered to be the rate-limiting enzyme in the synthesis of 2,3-butanediol. In this work, the enzymatic activity of ALDC from Enterobacter aerogenes ALDC (E.a.-ALDC) was fully characterized with enzyme kinetics, indicating a Km of 14.83 ± 0.87 mM and a kcat of 0.81 ± 0.09 s−1. However, compared with the activities of ALDCs reported from other bacteria, the activity of E.a.-ALDC was determined to present a relatively lower value of 849.08 ± 35.21 U/mg. The enzyme showed maximum activity at pH 5.5. In addition, the activity of E.a.-ALDC was promoted by Mg2+. The crystal structure of E.a.-ALDC firstly solved by X-ray crystallography at resolution of 2.4 Å revealed a chelated zinc ion with conserved His199, His201, His212, Glu70 and Glu259. In the active center, the conservative Arg150 was particularly proven to deviate from the zinc ion of the active centre, by adopting a flexible conformational change, resulting in a weak interaction network of the enzyme and the substrate. Further in silico docking of E.a.-ALDC with two enantiomers, (R)-acetolactate and (S)-acetolactate, unaltered the interaction network of E.a.-ALDC from the apo structure, which confirmed the weakened role of Arg150 in the catalytic properties of E.a.-ALDC. Our results reveal a unique structure-function relationship of acetolactate decarboxylase and provide a fundamental basis for the enzymatic synthesis of acetoin.

Three pairs of weak interactions precisely regulate the G-loop gate of Kir2.1 channel.

Kir2.1 (also known as IRK1) plays key roles in regulation of resting membrane potential and cell excitability. To achieve its physiological roles, Kir2.1 performs a series of conformational transition, named as gating. However, the structural basis of gating is still obscure. Here, we combined site-directed mutation, two-electrode voltage clamp with molecular dynamics simulations and determined that H221 regulates the gating process of Kir2.1 by involving a weak interaction network. Our data show that the H221R mutant accelerates the rundown kinetics and decelerates the reactivation kinetics of Kir2.1. Compared with the WT channel, the H221R mutation strengthens the interaction between the CD- and G-loops (E303-R221) which stabilizes the close state of the G-loop gate and weakens the interactions between C-linker and CD-loop (R221-R189) and the adjacent G-loops (E303-R312) which destabilizes the open state of G-loop gate. Our data indicate that the three pairs of interactions (E303-H221, H221-R189 and E303-R312) precisely regulate the G-loop gate by controlling the conformation of G-loop. Proteins 2016; 84:1929-1937. © 2016 Wiley Periodicals, Inc.

Entasis through hook-and-loop fastening in a glycoligand with cumulative weak forces stabilizing Cu(I).

The idea of a possible control of metal ion properties by constraining the coordination sphere geometry was introduced by Vallee and Williams with the concept of entasis, which is frequently postulated to be at stake in metallobiomolecules. However, the interactions controlling the geometry at metal centers remain often elusive. In this study, the coordination properties toward copper ions—Cu(II) or Cu(I)—of a geometrically constrained glycoligand centered on a sugar scaffold were compared with those of an analogous ligand built on an unconstrained alkyl chain. The sugar-centered ligand was shown to be more preorganized for Cu(II) coordination than its open-chain analogue, with an unusual additional stabilization of the Cu(I) redox state. This preference for Cu(I) was suggested to arise from geometric constraints favoring an optimized folding of the glycoligand minimizing steric repulsions. In other words, the Cu(I) d(10) species is stabilized by valence shell electron pair repulsion (VSEPR). This idea was rationalized by a theoretical noncovalent interactions (NCI) analysis. The cumulative effects of weak forces were shown to create an efficient buckle as in a hook-and-loop fastener, and fine structural features within the glycoligand reduce repulsive interactions for the Cu(I) state. This study emphasizes that monosaccharide platforms are appropriate ligand backbones for a delicate geometric control at the metal center, with a network of weak interactions within the ligand. This structuration availing in glycoligands makes them attractive for metallic entasis.

Effects of Nanoscale Confinement on the Functionality of Nucleic Acids: Implications for Nanomedicine

The facile self-assembly and nanomanipulation of nucleic acids hold great promise in the design of innovative, programmable materials, with applications ranging from biosensing to cellular targeting and drug delivery. Little is known, however, of the effects of confinement on biochemical reactions within such systems, in which the level of packing and crowding is similar to that of intracellular environments. In this review article we outline novel, unexpected properties of nucleic acids that arise from nanoscale confinement, as mainly revealed by atomic force and electron microscopy, electrochemistry, fluorescence spectroscopy, and gel electrophoresis. We review selected scientific studies over the last decade that describe the novel behavior of nanoconfined nucleic acids with respect to hybridization, denaturation, conformation, stability, and enzyme accessibility. The nanoscale systems discussed include self-assembled, water-soluble, DNA or RNA nanostructures, ranging in width from a few to several tens of nm; gold nanoparticles coated with DNA monolayers; and self-assembled monolayers of DNA, from a few to several hundreds of bp in length. These studies reveal that the functionality of nucleic acid-based nanosystems is highly dependent upon the local density, molecular flexibility and network of weak interactions between adjacent molecules. These factors significantly affect steric hindrance, molecular crowding and hydration, which in turn control nucleic acid hybridization, denaturation, conformation, and enzyme accessibility. The findings discussed in this review article demonstrate that nucleic acids function in a qualitatively different manner within nanostructured systems, and suggest that these novel properties, if better understood, will enable the development of powerful molecular tools for nanomedicine.

Electron and Spin Density Topology of the H‐Cluster and Its Biomimetic Complexes

AbstractThe catalytically active cluster of [FeFe]‐hydrogenase (H‐cluster) is unique due to its chemical composition and electronic and geometric structures. Protein crystallography revealed the presence of biologically unique diatomic ligands coordinating to the Fe centers and three light atoms bridging the sulfur atoms of its [2Fe]‐subcluster. The identity of the light atoms remains uncertain, even at close to atomic resolution (1.39 Å), as well as due to the lack of understanding at the molecular level of the cluster's biosynthetic pathway. By using all of the proposed ligand compositions, we carried out a comprehensive electronic structure analysis by evaluating the topology of the electron density and, particularly, the atomic spin density distribution derived from various population analysis methods for the free dithiolate ligands, the biomimetic [2Fe] complexes, and the entire H‐cluster embedded in its approximately 3.5 Å protein environment. In the biomimetic model complexes we found substantial spin density delocalization at the bridgehead of the dithiolate ligands. We attributed the presence of spin density to the through‐space spin polarization interaction between the paramagnetic iron centers and the bridgehead group, as represented by the ring critical points for the [Fe–(S–R–S)–Fe] metallacycles. However, this spin polarization of the bridgehead group vanishes for some of the biomimetic models, as well as for the 208‐atom computational model of the H‐cluster, due to a network of weak interactions. When the bridgehead group becomes part of a conduit for transmitting the spin polarization towards the terminal ends of each interaction network, such as the distal water or H‐bonded residues, the spin density vanishes. The variations of the Fe atomic spin densities were compared and contrasted for the proximal and distal iron sites in the crystallographic and the rotated conformations, respectively.

Cyclic Peptide–Polymer Complexes and Their Self‐Assembly

The efficient synthesis of novel chiral cyclic peptides cyclo[NHCHX-CH=CHCH(2)CO(NHCH(2)CH=CHCH(2)CO)(2)] designed to develop hydrogen-bonding interactions with suitable polymers is described. Complexation of a carboxylic acid derivatized cyclic peptide 2 (X = CH(2)OCOCH(2)CH(2)CO(2)H) capable of self-assembling as "endless" tubes, with poly(vinyl alcohol) (PVA) led to a vast weak-interaction network, in which the cyclopeptide developed extensive hydrogen-bonding interactions with the hydroxyl groups of PVA through not only the carboxylic acid, but also its ester carbonyl and amide groups. In aqueous solution, the peptide/PVA complexes self-assemble into long-grain ricelike aggregates compatible with the stacking of cyclic peptides through intercycle hydrogen bonds. Upon casting on silicon wafer, the anisotropic aggregates can coalesce to form filaments tens of micrometers long. The study demonstrates that complexing functionalized cyclic peptides with polymers through hydrogen bonding is a useful approach for using polymers to mediate the self-assembly and self-organization of cyclic peptides.

Three-dimensional Structure of the EphB2 Receptor in Complex with an Antagonistic Peptide Reveals a Novel Mode of Inhibition

The Eph family of receptor tyrosine kinases has been implicated in tumorigenesis as well as pathological forms of angiogenesis. Understanding how to modulate the interaction of Eph receptors with their ephrin ligands is therefore of critical interest for the development of therapeutics to treat cancer. Previous work identified a set of 12-mer peptides that displayed moderate binding affinity but high selectivity for the EphB2 receptor. The SNEW antagonistic peptide inhibited the interaction of EphB2 with ephrinB2, with an IC50 of approximately 15 microm. To gain a better molecular understanding of how to inhibit Eph/ephrin binding, we determined the crystal structure of the EphB2 receptor in complex with the SNEW peptide to 2.3-A resolution. The peptide binds in the hydrophobic ligand-binding cleft of the EphB2 receptor, thus competing with the ephrin ligand for receptor binding. However, the binding interactions of the SNEW peptide are markedly different from those described for the TNYL-RAW peptide, which binds to the ligand-binding cleft of EphB4, indicating a novel mode of antagonism. Nevertheless, we identified a conserved structural motif present in all known receptor/ligand interfaces, which may serve as a scaffold for the development of therapeutic leads. The EphB2-SNEW complex crystallized as a homodimer, and the residues involved in the dimerization interface are similar to those implicated in mediating tetramerization of EphB2-ephrinB2 complexes. The structure of EphB2 in complex with the SNEW peptide reveals novel binding determinants that could serve as starting points in the development of compounds that modulate Eph receptor/ephrin interactions and biological activities.

A Cobalt(III) Chiroporphyrin and Its Amine Adducts. A Potential Chiral NMR Shift Reagent for Amines.

The chlorocobalt(III) complex of alphabetaalphabeta-tetramethylchiroporphyrin, CoCl(TMCP), has been prepared as a potential enantioselective host or chiral NMR shift reagent for optically active amines. The X-ray structure of CoCl(OHCH(2)CH(3))(TMCP) shows the six-coordinate cobalt(III) ion at the center of a strongly ruffled porphyrin. The 2-fold-disordered ethanol ligand interacts with the chiroporphyrin host by two C-H.O hydrogen bonds to the carbonyl groups of two ester substituents. Primary amines bind to this diamagnetic cobalt(III) center to form cationic 2:1 complexes in which the (1)H NMR resonances of the axial ligands are shifted upfield of tetramethylsilane by the porphyrin ring current. Coordinated enantiopure 2-alkylamines exhibit NMR signals for the protons of the amine group which are characteristic of their (R or S) absolute configuration. The bis-complexes of the same amines in racemic form exist as three different species, (R,R), (S,S), and (R,S), in 1:1:2 relative ratios. Negligible enantioselection by the chiral host suggests kinetic control of bis(amine) complex formation on cobalt(III). The X-ray structure of the bis((S)-2-butylamine) complex [Co((S)-NH(2)CH(CH(3))CH(2)CH(3))(2)(TMCP)][CoCl(4)](0.5) shows a 2-fold-disordered amine on one face of the porphyrin only. The unique amine on the other face is held within the porphyrin groove by a network of weak interactions including N-H.O and C-H.O hydrogen bonds. With its ability to induce good resolution of axial ligand (1)H NMR resonances and slow dissociation kinetics of its bis-adducts, CoCl(TMCP) may be useful as a chiral NMR shift reagent for conformational studies of chiral amines and as an analytical reagent for the determination of their enantiomer composition.