Virtual screening for high affinity guests for synthetic supramolecular receptors

The protein/ligand docking software GOLD, which was originally developed for drug discovery, has been used in a virtual screen to identify small molecules that bind with extremely high affinities (K ≈ 107 M-1) in the cavity of a cubic coordination cage in water. A scoring function was developed using known guests as a training set and modified by introducing an additional term to take account of loss of guest flexibility on binding. This scoring function was then used in GOLD to successfully identify 15 new guests and accurately predict the binding constants. This approach provides a powerful predictive tool for virtual screening of large compound libraries to identify new guests for synthetic hosts, thereby greatly simplifying and accelerating the process of identifying guests by removing the reliance on experimental trial-and-error

Optimization of gold nanoparticle-based real-time colorimetric assay of dipeptidyl peptidase IV activity

Dipeptidyl peptidase IV (DPP-IV also referred to as CD-26) is a serine protease enzyme with remarkable diagnostic and prognostic value in a variety of health and disease conditions. Herein, we describe a simple and real-time colorimetric assay for DPP-IV/CD-26 activity based on the aggregation of gold nanoparticles (AuNPs) functionalized with the peptide substrates: Gly-Pro-Asp-Cys (GPDC) or Val-Pro-ethylene diamine-Asp-Cys (VP-ED-DC). Cleavage of the substrates by DPP-IV resulted in aggregation of the AuNPs with accompanying color change in the solution from red to blue that was monitored using either a UV–visible spectrophotometer or by the naked eye. Factors, such as time course of the reaction, stability of the functionalized AuNPs and the structure of the substrate that influence the cleavage reaction in solution were investigated. The effects of potential interference from serum proteins (lysozyme, thrombin and trypsin) on the analytical response were negligible. The detection limits when GPDC or VP-EN-DC functionalized AuNPs were used for DPP-IV assay were 1.2 U/L and 1.5 U/L, respectively. The VP-EN-DC method was preferred for the quantitative determination of DPP-IV activity in serum because of its wide linear range 0–30 U/L compared to 0–12 U/L for the GPDC assay. Recoveries from serum samples spiked with DPP-IV activity, between 5 and 25 U/L, and using the VP-EN-DC modified AuNPs method ranged between 83.6% and 114.9%. The two colorimetric biosensors described here are superior to other conventional methods because of their simplicity, stability, selectivity and reliability

Stepwise synthesis of mixed-metal assemblies using pre-formed Ru( ii ) ‘complex ligands’ as building blocks

Two families of heteronuclear coordination complexes have been prepared in a stepwise manner using pre-formed, kinetically inert [RuL3]2+ building blocks, in which L is a bis-bidentate bridging ligand with two pyrazole–pyridyl termini, coordinated at one end to the Ru(II) centre. These pre-formed ‘complex ligands’ – with three pendant binding sites – react with additional labile transition metal dications to complete the stepwise assembly of mixed-metal arrays in which labile [Co(II)/Cd(II)] or inert [Ru(II)] ions strictly alternate around the framework. When L = the thiophene-2,5-diyl spaced ligand Lth, the complex [Ru(Lth)3]2+ is formed in the expected 3[thin space (1/6-em)]:[thin space (1/6-em)]1 mer[thin space (1/6-em)]:[thin space (1/6-em)]fac ratio: reaction with labile Co(II) or Cd(II) ions completes formation of a heteronuclear square [Ru2Co2(Lth)6]8+ or one-dimensional coordination polymer {[CdRu(Lth)3]4+}∞, respectively. In these only the mer isomer of [Ru(Lth)3]2+ is selected by the self-assembly process, whereas the fac isomer is not used. When L = a 1,3-benzene-diyl spaced ligand (Lph), the complex ligand [Ru(Lph)3]2+ formed in the initial step is enriched in mer isomer (80–87% mer, depending on reaction conditions). Two quite different products were isolated from reaction of [Ru(Lph)3]2+ with Co(II) depending on the conditions. These are the rectangular, hexanuclear ‘open-book’ array [Ru3Co3(Lph)9]12+ which contains a 2[thin space (1/6-em)]:[thin space (1/6-em)]1 proportion of fac/mer Ru(II) metal centres; and the octanuclear cubic [Ru4Co4(Lph)12{Na(BF4)4}]13+ cage which is a new structural type containing all mer Ru(II) vertices and all fac Co(II) vertices. The cavity of this cubic cage contains a tetrahedral array of fluoroborate anions which in turn coordinate to a central Na(I) ion – an unusual example of a metal complex [Na(BF4)4]3− acting as the guest inside the cage-like metal complex [Ru4Co4(Lph)12]16+

A Quantitative Study of the Effects of Guest Flexibility on Binding Inside a Coordination Cage Host.

We have performed a systematic investigation of the effects of guest flexibility on their ability to bind in the cavity of a coordination cage host in water, using two sets of isomeric aliphatic ketones that differ only in the branching patterns of their alkyl chains. Apart from the expected increase in binding strength for C9 over C7 ketones associated with their greater hydrophobic surface area, within each isomeric set there is a clear inverse correlation between binding free energy and guest flexibility, associated with loss of conformational entropy. This can be parameterized by the number of rotatable C-C bonds in the guest, with each additional rotatable bond resulting in a penalty of around 2 kJ mol(-1) in the binding free energy, in good agreement with values obtained from protein/ligand binding studies. We used the binding data for the new flexible guests to improve the scoring function that we had previously developed that allowed us to predict binding constants of relatively rigid guests in the cage cavity using the molecular docking programme GOLD (Genetic Optimisation of Ligand Docking). This improved scoring function resulted in a significant improvement in the ability of GOLD to predict binding constants for flexible guests, without any detriment to its ability to predict binding for more rigid guests

Youth perspectives of schooling in a Northern-Ontario community

In Ontario, northern, rural youth face disadvantages due to their geographic location, as the majority of students attending high school, if not relocated to another community for their studies, must endure daily commutes ranging from 60 to 130 kilometers in order to attend classes. Yet, student-youths’ perspectives on how their geographic location influences their schooling experiences are currently absent from our understanding of educational equity in northern, rural contexts. While the literature on northern, rural education has focused almost exclusively on teacher, leadership and community perspectives, this study utilized a critical consciousness framework and interpretative phenomenology analysis with photovoice methods to explore youths’ perceptions of rural education. Five participants shared their thoughts and experiences through photovoice, individual interviews and focus groups to explore their rural educational experiences. The objective of this study was to illuminate the barriers to educational success from an equity standpoint and to explore innovative approaches with photovoice to capitalize on the strengths of these students in order to address disparities and to create opportunities for change in educational policy and practice. The findings highlighted some of the ways in which spatial, socio-cultural and physical obstacles to learning affect youth development while emphasizing how the school's climate and teachers contribute to fostering educational equity and a sense of belonging. Findings also revealed that youth encounter numerous challenges in their pursuit of secondary education. However, they manage to overcome these obstacles through the support of their schools, which serve as safe havens fostering strong relationships within the school community, or by benefiting from a flexible approach to their education. In the realm of equitable rural education, this study significantly contributes to the existing body of literature. Specifically, the present study implies that educational equity requires a lot of work. It encompasses various aspects, including a willingness to learn, cooperation, sharing of power, finding resources, harnessing creativity and imagination, and adjusting attitudes. Lastly, this study amplifies the voices of youth in the discourse surrounding educational equity in northern, rural schools

Binding of hydrophobic guests in a coordination cage cavity is driven by liberation of 'high-energy' water

The cavity of an M8L12 cubic coordination cage can accommodate a cluster of ten water molecules in which the average number of hydrogen bonds per water molecule is 0.5 H-bonds less than it would be in the bulk solution. The presence of these 'hydrogen-bond frustrated' or 'high-energy' water molecules in the cavity results in the hydrophobic effect associated with guest binding being predominantly enthalpy-based, as these water molecules can improve their hydrogen-bonding environment on release. This contrasts with the classical form of the hydrophobic effect in which the favourable entropy change associated with release of ordered molecules from hydrophobic surfaces dominates. For several guests Van't Hoff plots showed that the free energy of binding in water is primarily enthalpy-driven. For five homologous pairs of guests related by the presence or absence of a CH2 group, the incremental changes to ∆H and T∆S for guest binding ¬- i.e. ∆∆H and T∆∆S, the difference in contributions arising from the CH2 group - are consistently 5±1 kJ mol-1 for ∆∆H and 0±1 kJ mol-1 for T∆∆S. This systematic dominance of ∆H in the binding of hydrophobic guests is consistent with the view that guest binding is dominated by release of 'high energy' water molecules into a more favourable solvation environment, as has been demonstrated recently for some members of the cucurbituril family

Photoinduced energy- and electron-transfer from a photoactive coordination cage to bound guests.

In a coordination cage which contains an array of twelve naphthyl chromophores surrounding a central cavity, photoinduced energy or electron-transfer can occur from the chromophore array to the bound guest in supramolecular host/guest complexes

Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage.

The hollow cavities of coordination cages can provide an environment for enzyme-like catalytic reactions of small-molecule guests. Here, we report a new example (catalysis of the Kemp elimination reaction of benzisoxazole with hydroxide to form 2-cyanophenolate) in the cavity of a water-soluble M8L12 coordination cage, with two features of particular interest. First, the rate enhancement is among the largest observed to date: at pD 8.5, the value of kcat/kuncat is 2 × 10(5), due to the accumulation of a high concentration of partially desolvated hydroxide ions around the bound guest arising from ion-pairing with the 16+ cage. Second, the catalysis is based on two orthogonal interactions: (1) hydrophobic binding of benzisoxazole in the cavity and (2) polar binding of hydroxide ions to sites on the cage surface, both of which were established by competition experiments

Probing the limits of selectivity in a recognition-mediated reaction network embedded within a dynamic covalent library

This work was supported by the award of a Postgraduate Studentship from EPSRC (EP/K503162/1) to TK.Two recognition-mediated reaction processes operating through a reactive binary complex drive resolution of a 24-component dynamic covalent library, assembled from individual aldehydes and nucleophiles. The effectiveness of the library resolution and selective amplification of one recognition-enabled species over another is limited by the difference in the rates of the recognition-mediated reactive processes and strength of the recognition processes employed in the dynamic system.PostprintPeer reviewe

Mapping the internal recognition surface of an octanuclear coordination cage using guest libraries

Size and shape criteria for guest binding inside the cavity of an octanuclear cubic coordination cage in water have been established using a new fluorescence displacement assay to quantify guest binding. For aliphatic cyclic ketones of increasing size (from C5 to C11), there is a linear relationship between ΔG for guest binding and the guest’s surface area: the change in ΔG for binding is 0.3 kJ mol–1 Å–2, corresponding to 5 kJ mol–1 for each additional CH2 group in the guest, in good agreement with expectations based on hydrophobic desolvation. The highest association constant is K = 1.2 × 106 M–1 for cycloundecanone, whose volume is approximately 50% of the cavity volume; for larger C12 and C13 cyclic ketones, the association constant progressively decreases as the guests become too large. For a series of C10 aliphatic ketones differing in shape but not size, ΔG for guest binding showed no correlation with surface area. These guests are close to the volume limit of the cavity (cf. Rebek’s 55% rule), so the association constant is sensitive to shape complementarity, with small changes in guest structure resulting in large changes in binding affinity. The most flexible members of this series (linear aliphatic ketones) did not bind, whereas the more preorganized cyclic ketones all have association constants of 104–105 M–1. A crystal structure of the cage·cycloundecanone complex shows that the guest carbonyl oxygen is directed into a binding pocket defined by a convergent set of CH groups, which act as weak hydrogen-bond donors, and also shows close contacts between the exterior surface of the disc-shaped guest and the interior surface of the pseudospherical cage cavity despite the slight mismatch in shape