Molecular Recognition of Methionine-Terminated Peptides by Cucurbit[8]uril.

This Article describes the molecular recognition of peptides containing an N-terminal methionine (Met) by the synthetic receptor cucurbit[8]uril (Q8) in aqueous solution and with submicromolar affinity. Prior work established that Q8 binds with high affinity to peptides containing aromatic amino acids, either by simultaneous binding of two aromatic residues, one from each of two different peptides, or by simultaneous binding of an aromatic residue and its immediate neighbor on the same peptide. The additional binding interface of two neighboring residues suggested the possibility of targeting nonaromatic peptides, which have thus far bound only weakly to synthetic receptors. A peptide library designed to test this hypothesis was synthesized and screened qualitatively for Q8 binding using a fluorescent indicator displacement assay. The large fluorescence response observed for several Met-terminated peptides suggested strong binding, which was confirmed quantitatively by the determination of submicromolar equilibrium dissociation constant values for Q8 binding to MLA, MYA, and MFA using isothermal titration calorimetry (ITC). This discovery of high affinity binding to Met-terminated peptides and, more generally, to nonaromatic peptides prompted a detailed investigation of the determinants of binding in this system using ITC, electrospray ionization mass spectrometry, and 1H NMR spectroscopy for 25 purified peptides. The studies establish the sequence determinants required for high-affinity binding of Met-terminated peptides and demonstrate that cucurbit[ n]uril-mediated peptide recognition does not require an aromatic residue for high affinity. These results, combined with the known ability of cucurbit[ n]urils to target N-termini and disordered loops in folded proteins, suggest that Q8 could be used to target unmodified, Met-terminated proteins.

Electrochromic poly(acetylene)s with switchable visible/near-IR absorption characteristics.

Ferrocene is incorporated into a poly(acetylene) derivative via the postpolymerization amidation of a polymer precursor bearing pentafluorophenyl ester-leaving groups with aminoferrocene. While the neutral polymer exhibits a strong absorbance at 553 nm due to its conjugated backbone, oxidation of the ferrocene moieties with silver tetrafluoroborate causes the material to absorb in the near-IR (λ max ≈ 1215 nm). Subsequent reduction of the oxidized polymer with decamethylferrocene restores the initial absorbance profile, demonstrating that the material features switchable visible/near-IR absorption characteristics.

Redox-switchable ring-closing metathesis: catalyst design, synthesis, and study.

High yielding syntheses of 1-(ferrocenylmethyl)-3-mesitylimidazolium iodide (1) and 1-(ferrocenylmethyl)-3-mesitylimidazol-2-ylidene (2) were developed. Complexation of 2 to [{Ir(cod)Cl}2] (cod=cis,cis-1,5-cyclooctadiene) or [Ru(PCy3)Cl2(=CH-o-O-iPrC6H4)] (Cy=cyclohexyl) afforded 3 ([Ir(2)(cod)Cl]) and 5 ([Ru(2)Cl2(=CH-o-O-iPrC6H4)]), respectively. Complex 4 ([Ir(2)(CO)2Cl]) was obtained by bubbling carbon monoxide through a solution of 3 in CH2Cl2. Spectroelectrochemical IR analysis of 4 revealed that the oxidation of the ferrocene moiety in 2 significantly reduced the electron-donating ability of the N-heterocyclic carbene ligand (ΔTEP=9 cm(-1); TEP=Tolman electronic parameter). The oxidation of 5 with [Fe(η(5)-C5H4COMe)Cp][BF4] as well as the subsequent reduction of the corresponding product [5][BF4] with decamethylferrocene (Fc*) each proceeded in greater than 95% yield. Mössbauer, UV/Vis and EPR spectroscopy analysis confirmed that [5][BF4] contained a ferrocenium species, indicating that the iron center was selectively oxidized over the ruthenium center. Complexes 5 and [5][BF4] were found to catalyze the ring-closing metathesis (RCM) of diethyl diallylmalonate with observed pseudo-first-order rate constants (k(obs)) of 3.1×10(-4) and 1.2×10(-5) s(-1), respectively. By adding suitable oxidants or reductants over the course of a RCM reaction, complex 5 was switched between different states of catalytic activity. A second-generation N-heterocyclic carbene that featured a 1',2',3',4',5'- pentamethylferrocenyl moiety (10) was also prepared and metal complexes containing this ligand were found to undergo iron-centered oxidations at lower potentials than analogous complexes supported by 2 (0.30-0.36 V vs. 0.56-0.62 V, respectively). Redox switching experiments using [Ru(10)Cl2(=CH-o-O-iPrC6H4)] revealed that greater than 94% of the initial catalytic activity was restored after an oxidation-reduction cycle.

Blind prediction of host-guest binding affinities: a new SAMPL3 challenge.

The computational prediction of protein-ligand binding affinities is of central interest in early-stage drug-discovery, and there is a widely recognized need for improved methods. Low molecular weight receptors and their ligands--i.e., host-guest systems--represent valuable test-beds for such affinity prediction methods, because their small size makes for fast calculations and relatively facile numerical convergence. The SAMPL3 community exercise included the first ever blind prediction challenge for host-guest binding affinities, through the incorporation of 11 new host-guest complexes. Ten participating research groups addressed this challenge with a variety of approaches. Statistical assessment indicates that, although most methods performed well at predicting some general trends in binding affinity, overall accuracy was not high, as all the methods suffered from either poor correlation or high RMS errors or both. There was no clear advantage in using explicit versus implicit solvent models, any particular force field, or any particular approach to conformational sampling. In a few cases, predictions using very similar energy models but different sampling and/or free-energy methods resulted in significantly different results. The protonation states of one host and some guest molecules emerged as key uncertainties beyond the choice of computational approach. The present results have implications for methods development and future blind prediction exercises.

Synthesis and study of olefin metathesis catalysts supported by redox-switchable diaminocarbene[3]ferrocenophanes.

A redox-switchable ligand, N,N'-dimethyldiaminocarbene[3]ferrocenophane (5), was synthesized and incorporated into a series of Ir- and Ru-based complexes. Electrochemical and spectroscopic analyses of (5)Ir(CO)2Cl (15) revealed that 5 displayed a Tolman electronic parameter value of 2050 cm(-1) in the neutral state and 2061 cm(-1) upon oxidation. Moreover, inspection of X-ray crystallography data recorded for (5)Ir(cis,cis-1,5-cyclooctadiene)Cl (13) revealed that 5 was sterically less bulky (%V(Bur) = 28.4) than other known diaminocarbene[3]ferrocenophanes, which facilitated the synthesis of (5)(PPh3)Cl2Ru(3-phenylindenylid-1-ene) (18). Complex 18 exhibited quasi-reversible electrochemical processes at 0.79 and 0.98 V relative to SCE, which were assigned to the Fe and Ru centers in the complex, respectively, based on UV-vis and electron pair resonance spectroscopic measurements. Adding 2,3-dichloro-5,6-dicyanoquinone over the course of a ring-opening metathesis polymerization of cis,cis-1,5-cyclooctadiene catalyzed by 18 ([monomer]0/[18]0 = 2500) reduced the corresponding rate constant of the reaction by over an order of magnitude (pre-oxidation: k(obs) = 0.045 s(-1); post-oxidation: k(obs) = 0.0012 s(-1)). Subsequent reduction of the oxidized species using decamethylferrocene restored catalytic activity (post-reduction: k(obs) = up to 0.016 s(-1), depending on when the reductant was added). The difference in the polymerization rates was attributed to the relative donating ability of the redox-active ligand (i.e., strongly donating 5 versus weakly donating 5(+)) which ultimately governed the activity displayed by the corresponding catalyst.

1,1'-Bis(N-benzimidazolylidene)ferrocene: synthesis and study of a novel ditopic ligand and its transition metal complexes.

Diiridum complexes containing 1,1'-bis(N-benzimidazolylidene)ferrocene, a novel ditopic ligand comprised of two N-heterocyclic carbenes (NHCs) linked directly via their N-substituents to each cyclopentadienyl ring of a ferrocene moiety, were synthesized. Crystallographic analyses of these C(2)-symmetric bimetallic complexes revealed the benzimidazolylidene moieties were intramolecularly stacked in nearly opposing orientations, effectively forming Janus-type bis(NHC) structures in the solid state. Using a variety of electrochemical techniques, the oxidation potentials of the ferrocenyl groups in these complexes were found to depend on the auxillary ligands coordinated to the Ir centers (i.e., 1,5-cyclooctadiene vs. carbonyl). Similarly, the nu(CO) of carbonyls ligated to the Ir centers varied in accord with the oxidation state of the ferrocene contained with the bis(NHC) ligand. These results suggest that the Ir and Fe centers in these complexes are electronically coupled and that the electron donating ability of the bis(NHC) ligand reported herein can be tuned electrochemically.