Learning from nature: beta-sheet-mimicking copolymers get organized

The solution structures formed by coil-coil copolymers arise from the selective solvation of one of the two blocks and have been well described. In most cases in such relatively simple synthetic structures there are no specific attractive forces that can aid the aggregation process. Nature, however, provides plenty of inspiring polymeric architectures that are shaped and ordered hierarchically by noncovalent forces. The high level of structural definition displayed by proteins, for example, is unmatched by synthetic polymers. An emerging area of interest in polymer science tries to combine the best of both worlds, the natural and the synthetic, by conjugating synthetic polymers and beta-sheet-forming peptides. Understanding the supramolecular organization of the block copolymers driven exclusively by the intermolecular attractive forces of the peptide sequence is of particular interest. Not only do these peptide-polymer hybrid structures present an interesting new class of materials, they can also provide important insights into self-organization processes prevalent in nature.     

Differentiation of Boc- alpha,beta- and beta,alpha-peptides and a pair of diastereomeric beta,alpha-dipeptides by positive and negative ion electrospray tandem mass spectrometry (ESI-MS/MS)

Positive and negative ion electrospray ionization (ESI) tandem mass spectral study of a new series of hybrid peptides, viz, BocN-alpha,beta-peptides and BocN-beta,alpha-peptides, synthesized from C-linked carbo-beta3-amino acids [Caa (S)] and L-Ala has been carried out. The alpha,beta-peptides have been differentiated from beta,alpha-peptides by the collision-induced dissociation (CID) of [M + H]+ and [M - H]- ions in positive and negative ion ESI-MS respectively. The fragment ion [M + H - C(CH3)3 + H]+ formed from [M + H]+ ions by the loss of 2-methyl-prop-2-ene in alpha,beta-peptides with L-Ala at the N-terminus is insignificant or totally absent for beta,alpha-peptides which have the Caa (S) at N-terminus. The fragment ion [M - H-C(CH3)3OH - HNCO]- formed from [M - H]- of beta,alpha-peptide acids is totally absent for alpha,beta-peptide acids. This has been attributed to the absence of the beta-methylene group in alpha,beta-peptides, and the participation of the beta-methylene group in the loss of HNCO in beta,alpha-peptide acids is confirmed by the deuteration experiments. The CID of [M + H-Boc + H]+ ions of these peptides also produce characteristic fragmentation. In the CID spectra of alpha,beta-peptides, the b(n)+ ions and the resulting y(n)+ ions occur at a mass difference of 243 and 71 Da corresponding to the successive losses of Caa and L-Ala, whereas a mass difference of 71 and 243 Da is observed for beta,alpha-peptides. In contrast to the CID of protonated peptides, the CID of [M - H]- ions of the alpha,beta- and beta,alpha-peptide acids do not give b(n)- ions and show abundant z(n) (-) ions. Further, a pair of diastereomeric dipeptide esters and acids have been distinguished by the CID of [M + H]+ ions. The loss of 2-methyl-prop-2-ene is more pronounced for Boc-NH-Caa(R)-D-Ala-OCH3 (21) and Boc-NH-Caa(R)-D-Ala-OH (23) with Caa (R) at the N-terminus, whereas it is totally absent for Boc-NH-Caa (S)-D-Ala-OCH3 (22) and Boc-NH-Caa(S)-D-Ala-OH (24) peptides, which have Caa (S) at the N-terminus. Thus, on the basis of our previous and present studies, we propose that the CID of [M + H]+ ions provides a simple and useful method for distinguishing the configuration of Caa (S or R) at the N-terminus of BocN-carbo beta,alpha- and beta,beta-dipeptides.     

Conformer-independent ureidoimidazole motifs--tools to probe conformational and tautomeric effects on the molecular recognition of triply hydrogen-bonded heterodimers

Linear arrays of hydrogen bonds are useful for the reversible assembly of “stimuli‐responsive” supramolecular materials. There is thus an ongoing requirement for easy‐to‐synthesise motifs that are capable of presenting hydrogen‐bonding functionality in a predictable manner, such that high‐affinity and high‐fidelity recognition occurs. The design of linear arrays is made challenging as a consequence of their ability to adopt multiple conformational and tautomeric configurations; with each additional hydrogen‐bonding heteroatom added to an array, the available tautomeric and conformational space increases and it can be difficult to anticipate where unproductive conformers/tautomers will arise. This paper describes a detailed study on the complementary ureidoimidazole donor–donor–acceptor (DDA) array ( 1 ) and amidoisocytosine donor–acceptor–acceptor (DAA) array ( 2 ). A specific feature of 1 is that two degenerate, intramolecular hydrogen‐bonded conformations are postulated, both of which present a DDA array that is complementary to appropriate DAA partners. 1D and 2D ¹H NMR spectroscopy, isothermal titration calorimetry, and ab initio structure calculations confirm 1 interacts with 2 (K_a≈33000 M ^?1 in CDCl₃) in a conformer‐independent fashion driven by enthalpy. Comparison of the binding behaviour of 1 with hexylamidocytosine ( 4 ) and amidonaphthyridine ( 5 ) provides insight on the role that intramolecular hydrogen‐bonding plays in mediating affinity towards DAA partners.     

Comparative analyses of a family of potential self-replicators: the subtle interplay between molecular structure and the efficacy of self-replication

It is envisioned that protocols based on self-replication will emerge as a formidable synthetic apparatus for the production of nanoscale assemblies through molecular structures that are capable of automultiplication with high reaction rates and selectivities. To achieve this goal, a complete understanding of the relationship between molecular structure and replication efficiency is necessary. Rigorous experimental and theoretical analyses of a series of self-complementary scaffolds that are intimately related in a constitutional sense, manufactured through the Diels-Alder reaction of complementary subunits, were undertaken. Experimental and computational methods were employed to map the key determinants that dictate the emergence of self-replicative function, as well as the efficiency, rate and selectivity of the self-replicative processes.     

Biquinolino-modified beta-cyclodextrin dimers and their metal complexes as efficient fluorescent sensors for the molecular recognition of steroids

A series of bridged beta-cyclodextrin (beta-CyD) dimers possessing functional tethers of various lengths was synthesized in moderate yield by the treatment of 2,2'-biquinoline- 4,4'-dicarboxylic dichloride with beta-CyD or mono[6-oligo(ethylenediamino)-6-deoxy]-beta-CyDs. The products were 2,2'-biquinoline-4,4'-dicarboxy-bridged bis(6-O-beta-CyD) (8), N,N'-bis(2-aminoethyl)-2,2'-biquinoline-4,4'-dicarboxamide-bridged bis(6-amino-6-deoxy-beta-CyD) (9), and N,N'-bis(5-amino-3-azapentyl)-2,2'-biquinoline-4,4'-dicarboxamide-bridged bis(6-amino-6-deoxy-beta-CyD) (10). The reaction of 8-10 with copper perchlorate give their copper(II) complexes 11-13 in satisfactory yields of over 77 %. All the bis(beta-CyD)s 8-13 act as efficient fluorescent sensors and display remarkable fluorescence enhancement upon addition of optically inert steroids. The inclusion complexation behaviors of 8-13 when treated with the representative steroids cholate (14), deoxycholate (15), and glycocholate (16) in aqueous solution at 25 degrees C were investigated by means of UV/Vis spectroscopy, conductivity and fluorescence measurements, circular dichroism spectroscopy, and 2D NMR spectroscopy. The tether length of bis(beta-CyD) 9 allows it to adopt a cooperative host-tether-guest binding mode in which the spacer and guest are co-included in the two CyD cavities. As a result of this cooperation, 9 has a stability constant (K(s)) about 2x10(2) times higher than that of monomodified beta-CyD 4 for inclusion complexation with cholate. Metallooligo(beta-CyD)s with four beta-CyD units have enhanced binding abilities compared with monomodified beta-CyDs. These metallo compounds have binding affinities for guest steroids that are up to 50-4.1x10(3) times higher than those of CyDs 2-4. The guest-induced fluorescence enhancement of bis(CyD)s opens a new channel for the design of sensor materials. The complex stability constants of these compounds are discussed from the viewpoint of induced-fit interaction and cooperative multiple binding between host and guest.     

Structure and stability of beta-pleated sheets

Beside alpha-helices, beta-sheets are the most common secondary structure elements of proteins. In this article, the question of structure and stability of parallel and antiparallel sheets of various lengths is addressed. All data obtained are compared to a selected set of protein structures. In antiparallel beta-sheets, one of the two possible H-bonded structures (containing 14 atoms in the H-bonded pseudoring) is energetically more favored and also more abundant in proteins than the other one (with 10 atoms involved in the pseudoring). Parallel beta-sheets and their subunits are energetically less stable and indeed found to occur more rarely in proteins. Antiparallel hairpins are disfavored compared to beta-sheets formed by sequentially separated strands. Agreement between theory and experimental data indicates that characterization of structural building blocks at an appropriately accurate level of theory is a useful tool to get insight into fundamentals of protein structure.     

Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo-beta-lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry

Using the polarizable molecular mechanics method SIBFA, we have performed a search for the most stable binding modes of D- and L-thiomandelate to a 104-residue model of the metallo-beta-lactamase from B. fragilis, an enzyme involved in the acquired resistance of bacteria to antibiotics. Energy balances taking into account solvation effects computed with a continuum reaction field procedure indicated the D-isomer to be more stably bound than the L-one, conform to the experimental result. The most stably bound complex has the S(-) ligand bridging monodentately the two Zn(II) cations and one carboxylate O(-) H-bonded to the Asn193 side chain. We have validated the SIBFA energy results by performing additional SIBFA as well as quantum chemical (QC) calculations on small (88 atoms) model complexes extracted from the 104-residue complexes, which include the residues involved in inhibitor binding. Computations were done in parallel using uncorrelated (HF) as well as correlated (DFT, LMP2, MP2) computations, and the comparisons extended to corresponding captopril complexes (Antony et al., J Comput Chem 2002, 23, 1281). The magnitudes of the SIBFA intermolecular interaction energies were found to correctly reproduce their QC counterparts and their trends for a total of twenty complexes.     

A competitive molecular recognition study: syntheses and analysis of supramolecular assemblies of 3,5-dihydroxybenzoic acid and its bromo derivative with some N-donor compounds

A molecular recognition study of 3,5-dihydroxybenzoic acid (1) and its bromo derivative 4-bromo-3,5-dihydroxybenzoic acid (2) with the N-donor compounds 1,2-bis(4-pyridyl)ethene (bpyee), 1,2-bis(4-pyridyl)ethane (bpyea), and 4,4'-bipyridine (bpy) is reported. Thus, the syntheses and structural analysis of molecular adducts 1 a-1 c (1 with bpyee, bpyea, and bpy, respectively) and 2 a-2 c (2 with bpyee, bpyea, and bpy, respectively) are discussed. In all these adducts, recognition between the constituents is established through either O--H...N and/or O--H...N/C--H...O pairwise hydrogen bonds. In all the adducts both OH and COOH functional groups available on 1 and 2 interact with the N-donor compounds, except in 2 a, in which only COOH (COO-) is involved in the recognition process. The COOH moieties in 1 a, 1 b, and 2 b form only single O--H...N hydrogen bonds, whereas in 1 c and 2 c, they form pairwise O--H...N/C--H...O hydrogen bonds. In addition, subtle differences in the recognition patterns resulted in the formation of cyclic networks of different dimensions. In fact, only 1 c forms a four-molecule cyclic moiety, as was already documented in the literature for this kind of assemblies. All complexes have been characterized by single-crystal X-ray diffraction. The supramolecular architectures are quite elegant and simple, with stacking of sheets in all adducts, but a rather complex network with a threefold interpenetration pattern was found in 2 c.     

Combination self-assembly of β-sheet peptides and carbon nanotubes: functionalizing carbon nanotubes with bioactive β-sheet block copolypeptides

Understanding the self-assembly behavior of β-sheet peptides is important, not only in constructing bioactive peptide nanostructures, but also in inhibiting uncontrollable protein aggregation in protein-misfolding diseases. Here, the first systematic investigation of combination self-assembly between β-sheet block copolypeptides and CNTs is presented, demonstrating the presence of several different association modes during the combination self-assembly process. Bioactive β-sheet block copolypeptides can self-assemble by themselves, or can be used to functionalize CNT hybrids depending on the situation. This behavior may be important both for fabricating bioactive peptide/CNT hybrids and for controlling/inhibiting protein-misfolding diseases.     

Nucleotide recognition in water by a guanidinium-based artificial tweezer receptor

The water-soluble tweezer receptor 1 with two symmetric peptidic arms, which are connected by an aromatic scaffold and contain lysine, phenylalanine, and a guanidinium-based anion-binding site as headgroup, has been synthesized. UV/Vis-derived Job plots show that the receptor forms 1:1 complexes with nucleotides and phosphate in buffered water at neutral pH. Binding constants have been determined by fluorescence and UV/Vis spectroscopy. All nucleotides tested were bound very efficiently, even in pure water, with binding constants between 10(4) and 10(5) M(-1) . Interestingly, all mononucleotides were bound much stronger than phosphate by a factor of at least 5 to 10. Furthermore 1 favors the binding of adenosine monophosphate (AMP) over adenosine diphosphate (ADP) and adenosine triphosphate (ATP), which is unprecedented for artificial nucleotide receptors reported so far. According to NMR spectroscopy and molecular modeling studies, the efficient binding is a result of strong electrostatic contacts supported by π-π interactions with the nucleobase within the cavity-shaped receptor.     

Molecular Dynamics Simulations of Small Peptides: Can One Derive Conformational Preferences from ROESY Spectra?

Folding properties of beta-peptides were investigated by means of NMR experiments and MD simulations of beta-dipeptides, which serve as small test systems to study the influence of stereocenters and side chains on hydrogen-bond and consequently on secondary-structure formation. Two stereoisomers, SR and SS, of a Val-Phe dipeptide, and of the corresponding Ala-Ala dipeptide, and a Gly-Gly dipeptide were simulated in methanol for 40 ns. In agreement with experiment, the isomers of the Val-Phe dipeptide adopt quite different conformers at 298 K, the differences being reduced at 340 K. Interestingly, the SR isomer shows enhanced hydrogen bonding at the higher temperature. The adopted conformations are primarily determined by the R or S side chain substitution, and less by the type of side chain. Back-calculation of (1)H ROESY spectra and (3)J coupling constants from the MD simulations and comparison with the experimental data for the Val-Phe dipeptides shows good agreement between simulation and experiment, and reveals possible problems and pitfalls, when deriving structural properties of a small and extremely flexible molecule from NMR data only. Inclusion of all aspects of internal dynamics is essential to the correct prediction of the NMR spectra of these small molecules. Cross comparison of calculated with experimental spectra for both isomers shows that only a few out of many ROESY peaks reflect the sizeable conformational differences between the isomers at 298 K.