Co-reporter:Ivica Cvrtila, Hugo Fanlo-Virgós, Gaël Schaeffer, Guillermo Monreal Santiago, and Sijbren Otto
Journal of the American Chemical Society September 13, 2017 Volume 139(Issue 36) pp:12459-12459
Publication Date(Web):July 27, 2017
DOI:10.1021/jacs.7b03724
Photoisomerization provides a clean and efficient way of reversibly altering physical properties of chemical systems and injecting energy into them. These effects have been applied in development of systems such as photoresponsive materials, molecular motors, and photoactivated drugs. Typically, switching from more to less stable isomer(s) is performed by irradiation with UV or visible light, while the reverse process proceeds thermally or by irradiation using another wavelength. In this work we developed a method of rapid and tunable Z→E isomerization of C═N bond in acyl hydrazones, using aromatic thiols as nucleophilic catalysts. As thiols can be oxidized into catalytically inactive disulfides, the isomerization rates can be controlled via the oxidation state of the catalyst, which, together with the UV irradiation, provides orthogonal means to control the E/Z state of the system. As a proof of this concept, we have applied this method to control the diversity of acyl hydrazone based dynamic combinatorial libraries.
Co-reporter:Bartosz M. Matysiak, Piotr Nowak, Ivica Cvrtila, Charalampos G. Pappas, Bin Liu, Dávid Komáromy, and Sijbren Otto
Journal of the American Chemical Society May 17, 2017 Volume 139(Issue 19) pp:6744-6744
Publication Date(Web):April 25, 2017
DOI:10.1021/jacs.7b02575
The ability to design reaction networks with high, but addressable complexity is a necessary prerequisite to make advanced functional chemical systems. Dynamic combinatorial chemistry has proven to be a useful tool in achieving complexity, however with some limitations in controlling it. Herein we introduce the concept of antiparallel chemistries, in which the same functional group can be channeled into one of two reversible chemistries depending on a controllable parameter. Such systems allow both for achieving complexity, by combinatorial chemistry, and addressing it, by switching from one chemistry to another by controlling an external parameter. In our design the two antiparallel chemistries are thiol–disulfide exchange and thio-Michael addition, sharing the thiol as the common building block. By means of oxidation and reduction the system can be reversibly switched from predominantly thio-Michael chemistry to predominantly disulfide chemistry, as well as to any intermediate state. Both chemistries operate in water, at room temperature, and at mildly basic pH, which makes them a suitable platform for further development of systems chemistry.
Co-reporter:Pim W. J. M. Frederix, Julien Idé, Yigit Altay, Gaël Schaeffer, Mathieu Surin, David Beljonne, Anna S. Bondarenko, Thomas L. C. Jansen, Sijbren Otto, and Siewert J. Marrink
ACS Nano August 22, 2017 Volume 11(Issue 8) pp:7858-7858
Publication Date(Web):July 19, 2017
DOI:10.1021/acsnano.7b02211
Self-replication at the molecular level is often seen as essential to the early origins of life. Recently a mechanism of self-replication has been discovered in which replicator self-assembly drives the process. We have studied one of the examples of such self-assembling self-replicating molecules to a high level of structural detail using a combination of computational and spectroscopic techniques. Molecular Dynamics simulations of self-assembled stacks of peptide-derived replicators provide insights into the structural characteristics of the system and serve as the basis for semiempirical calculations of the UV–vis, circular dichroism (CD) and infrared (IR) absorption spectra that reflect the chiral organization and peptide secondary structure of the stacks. Two proposed structural models are tested by comparing calculated spectra to experimental data from electron microscopy, CD and IR spectroscopy, resulting in a better insight into the specific supramolecular interactions that lead to self-replication. Specifically, we find a cooperative self-assembly process in which β-sheet formation leads to well-organized structures, while also the aromatic core of the macrocycles plays an important role in the stability of the resulting fibers.Keywords: molecular dynamics; nanostructures; peptides; self-assembly; self-replication; simulation; spectroscopy;
Co-reporter:Sijbren Otto
Chem 2017 Volume 2, Issue 2(Volume 2, Issue 2) pp:
Publication Date(Web):9 February 2017
DOI:10.1016/j.chempr.2017.01.018
Sijbren Otto received his PhD in 1998 from the University of Groningen under the supervision of Jan Engberts and was a postdoc with Steve Regen at Lehigh University and Jeremy Sanders at the University of Cambridge, where he also started his independent career in 2001. In 2009 he returned to the University of Groningen, where he is currently a professor of systems chemistry.
Co-reporter:Dávid Komáromy;Meniz Tezcan;Dr. Gaël Schaeffer;Ivana Marić; Sijbren Otto
Angewandte Chemie International Edition 2017 Volume 56(Issue 46) pp:14658-14662
Publication Date(Web):2017/11/13
DOI:10.1002/anie.201707191
AbstractIn living systems processes like genome duplication and cell division are carefully synchronized through subsystem coupling. If we are to create life de novo, similar control over essential processes such as self-replication need to be developed. Here we report that coupling two dynamic combinatorial subsystems, featuring two separate building blocks, enables effector-mediated control over self-replication. The subsystem based on the first building block shows only self-replication, whereas that based on the second one is solely responsive toward a specific external effector molecule. Mixing the subsystems arrests replication until the effector molecule is added, resulting in the formation of a host–effector complex and the liberation of the building block that subsequently engages in self-replication. The onset, rate and extent of self-replication is controlled by the amount of effector present.
Co-reporter:Giulia Leonetti
Journal of the American Chemical Society 2015 Volume 137(Issue 5) pp:2067-2072
Publication Date(Web):January 13, 2015
DOI:10.1021/ja512644f
In Darwinian evolution, species that are better adapted to their environment win the competition for common resources from less well-adapted competitors. Thus, in such scenarios the nature of the environment may dictate the outcome of the competition. We investigated to what degree these biological principles acting at the level of species extend to the molecular level into systems based on fully synthetic self-replicating molecules. We now report two systems in which two replicators compete for a common building block and where the environment dictates which of the two replicators wins. We observed that subtle changes in the environment can lead to dramatic differences in the outcome of the competition.
Co-reporter:Piotr Nowak; Mathieu Colomb-Delsuc; Sijbren Otto;Jianwei Li
Journal of the American Chemical Society 2015 Volume 137(Issue 34) pp:10965-10969
Publication Date(Web):July 20, 2015
DOI:10.1021/jacs.5b04380
Self-assembly of a specific member of a dynamic combinatorial library (DCL) may lead to self-replication of this molecule. However, if the concentration of the potential replicator in the DCL fails to exceed its critical aggregation concentration (CAC), then self-replication will not occur. We now show how addition of a template can raise the concentration of a library member–template complex beyond its CAC, leading to the onset of self-replication. Once in existence, the replicator aggregates promote further replication also in the absence of the template that induced the initial emergence of the replicator.
Co-reporter:Dr. Jianwei Li;Piotr Nowak ;Dr. Sijbren Otto
Angewandte Chemie International Edition 2015 Volume 54( Issue 3) pp:833-837
Publication Date(Web):
DOI:10.1002/anie.201408907
Abstract
Allosteric synthetic receptors are difficult to access by design. Herein we report a dynamic combinatorial strategy towards such systems based on the simultaneous use of two different templates. Through a process of simultaneous casting (the assembly of a library member around a template) and molding (the assembly of a library member inside the binding pocket of a template), a Russian-doll-like termolecular complex was obtained with remarkable selectivity. Analysis of the stepwise formation of the complex indicates that binding of the two partners by the central macrocycle exhibits significant positive cooperativity. Such allosteric systems represent hubs that may have considerable potential in systems chemistry.
Co-reporter:Piotr Nowak;Dr. Vittorio Saggiomo;Dr. Fatemeh Salehian;Mathieu Colomb-Delsuc;Dr. Yang Han ;Dr. Sijbren Otto
Angewandte Chemie International Edition 2015 Volume 54( Issue 14) pp:4192-4197
Publication Date(Web):
DOI:10.1002/anie.201409667
Abstract
We have developed a method for the localized functionalization of gold nanoparticles using imine-based dynamic combinatorial chemistry. By using DNA templates, amines were grafted on the aldehyde-functionalized nanoparticles only if and where the nanoparticles interacted with the template molecules. Functionalization of the nanoparticles was controlled solely by the DNA template; only amines capable of interacting with DNA were bound to the surface. Interestingly, even though our libraries contained only a handful of simple amines, the DNA sequence influenced their attachment to the surface. Our method opens up new opportunities for the synthesis of multivalent, nanoparticle-based receptors for biomacromolecules.
Co-reporter:Piotr Nowak;Dr. Vittorio Saggiomo;Dr. Fatemeh Salehian;Mathieu Colomb-Delsuc;Dr. Yang Han ;Dr. Sijbren Otto
Angewandte Chemie 2015 Volume 127( Issue 14) pp:4266-4271
Publication Date(Web):
DOI:10.1002/ange.201409667
Abstract
We have developed a method for the localized functionalization of gold nanoparticles using imine-based dynamic combinatorial chemistry. By using DNA templates, amines were grafted on the aldehyde-functionalized nanoparticles only if and where the nanoparticles interacted with the template molecules. Functionalization of the nanoparticles was controlled solely by the DNA template; only amines capable of interacting with DNA were bound to the surface. Interestingly, even though our libraries contained only a handful of simple amines, the DNA sequence influenced their attachment to the surface. Our method opens up new opportunities for the synthesis of multivalent, nanoparticle-based receptors for biomacromolecules.
Co-reporter:Yang Han, Piotr Nowak, Mathieu Colomb-Delsuc, Manuel Pernia Leal, and Sijbren Otto
Langmuir 2015 Volume 31(Issue 46) pp:12658-12663
Publication Date(Web):October 30, 2015
DOI:10.1021/acs.langmuir.5b03673
The application of nanoparticles to the multivalent recognition of biomacromolecules or programmed self-assembly requires control over the relative placement of chemical groups on their surface. We have developed a method to direct the functionalization of surfaces of aldehyde-equipped gold nanoparticles using a DNA template. An error-correction mechanism is built into the functionalization process thanks to the thermodynamic control enabled by the hydrazone exchange reaction. This reversible reaction can be conveniently switched off by removing the catalyst, preserving the functionalization.
Co-reporter:Dr. Jianwei Li;Piotr Nowak ;Dr. Sijbren Otto
Angewandte Chemie 2015 Volume 127( Issue 3) pp:847-851
Publication Date(Web):
DOI:10.1002/ange.201408907
Abstract
Allosteric synthetic receptors are difficult to access by design. Herein we report a dynamic combinatorial strategy towards such systems based on the simultaneous use of two different templates. Through a process of simultaneous casting (the assembly of a library member around a template) and molding (the assembly of a library member inside the binding pocket of a template), a Russian-doll-like termolecular complex was obtained with remarkable selectivity. Analysis of the stepwise formation of the complex indicates that binding of the two partners by the central macrocycle exhibits significant positive cooperativity. Such allosteric systems represent hubs that may have considerable potential in systems chemistry.
Co-reporter:Jianwei Li, Piotr Nowak, Hugo Fanlo-Virgós and Sijbren Otto
Chemical Science 2014 vol. 5(Issue 12) pp:4968-4974
Publication Date(Web):20 Aug 2014
DOI:10.1039/C4SC01998A
A new azobenzene-based dithiol building block was developed which, upon oxidation, forms predominantly a [2]catenane consisting of two interlocked trimers. In the presence of cyclodextrin templates a series of [2] and [3]catenanes was formed instead. We developed a method that enabled estimating the equilibrium constants for catenation in all of these systems. The formation of the [3]catenanes is either cooperative or anticooperative, depending on the nature of the cyclodextrin. Using molecular dynamics simulations, we linked positive and negative cooperativity to, respectively, burying and exposure of hydrophobic surfaces upon catenation. Our results underline the importance of directly quantifying noncovalent interactions within catenanes, as the corresponding pseudo-rotaxane model systems were found to be poor predictors of binding interactions in the actual catenane.
Co-reporter:Dr. Jianwei Li;Ivica Cvrtila;Mathieu Colomb-Delsuc;Dr. Edwin Otten ;Dr. Sijbren Otto
Chemistry - A European Journal 2014 Volume 20( Issue 48) pp:15709-15714
Publication Date(Web):
DOI:10.1002/chem.201404977
Abstract
New methodology for making novel materials is highly desirable. Here, an “ingredients” approach to functional self-assembled hydrogels was developed. By designing a building block to contain the right ingredients, a multi-responsive, self-assembled hydrogel was obtained through a process of template-induced self-synthesis in a dynamic combinatorial library. The system can be switched between gel and solution by light, redox reactions, pH, temperature, mechanical energy and sequestration or addition of MgII salt.
Co-reporter:Hugo Fanlo-Virgós;Dr. Andrea-Nekane R. Alba;Saleh Hamieh;Mathieu Colomb-Delsuc ;Dr. Sijbren Otto
Angewandte Chemie 2014 Volume 126( Issue 42) pp:11528-11532
Publication Date(Web):
DOI:10.1002/ange.201403480
Abstract
In biology enzyme concentrations are continuously regulated, yet for synthetic catalytic systems such regulatory mechanisms are underdeveloped. We now report how a substrate of a chemical reaction induces the formation of its own catalyst from a dynamic molecular network. After complete conversion of the substrate, the network disassembles the catalyst. These results open up new opportunities for controlling catalysis in synthetic chemical systems.
Co-reporter:Hugo Fanlo-Virgós;Dr. Andrea-Nekane R. Alba;Saleh Hamieh;Mathieu Colomb-Delsuc ;Dr. Sijbren Otto
Angewandte Chemie International Edition 2014 Volume 53( Issue 42) pp:11346-11350
Publication Date(Web):
DOI:10.1002/anie.201403480
Abstract
In biology enzyme concentrations are continuously regulated, yet for synthetic catalytic systems such regulatory mechanisms are underdeveloped. We now report how a substrate of a chemical reaction induces the formation of its own catalyst from a dynamic molecular network. After complete conversion of the substrate, the network disassembles the catalyst. These results open up new opportunities for controlling catalysis in synthetic chemical systems.
Co-reporter:Jianwei Li ; Piotr Nowak
Journal of the American Chemical Society 2013 Volume 135(Issue 25) pp:9222-9239
Publication Date(Web):June 3, 2013
DOI:10.1021/ja402586c
Dynamic combinatorial chemistry (DCC) is a subset of combinatorial chemistry where the library members interconvert continuously by exchanging building blocks with each other. Dynamic combinatorial libraries (DCLs) are powerful tools for discovering the unexpected and have given rise to many fascinating molecules, ranging from interlocked structures to self-replicators. Furthermore, dynamic combinatorial molecular networks can produce emergent properties at systems level, which provide exciting new opportunities in systems chemistry. In this perspective we will highlight some new methodologies in this field and analyze selected examples of DCLs that are under thermodynamic control, leading to synthetic receptors, catalytic systems, and complex self-assembled supramolecular architectures. Also reviewed are extensions of the principles of DCC to systems that are not at equilibrium and may therefore harbor richer functional behavior. Examples include self-replication and molecular machines.
Co-reporter:Morteza Malakoutikhah ; Jérôme J.-P. Peyralans ; Mathieu Colomb-Delsuc ; Hugo Fanlo-Virgós ; Marc C. A. Stuart
Journal of the American Chemical Society 2013 Volume 135(Issue 49) pp:18406-18417
Publication Date(Web):November 12, 2013
DOI:10.1021/ja4067805
A family of self-replicating macrocycles was developed using dynamic combinatorial chemistry. Replication is driven by self-assembly of the replicators into fibrils and relies critically on mechanically induced fibril fragmentation. Analysis of separate dynamic combinatorial libraries made from one of six peptide-functionalized building blocks of different hydrophobicity revealed two selection criteria that govern the emergence of replicators from these systems. First, the replicators need to have a critical macrocycle size that endows them with sufficient multivalency to enable their self-assembly into fibrils. Second, efficient replication occurs only for library members that are of low abundance in the absence of a replication pathway. This work has led to spontaneous emergence of replicators with unrivalled structural complexity, being built from up to eight identical subunits and reaching a MW of up to 5.6 kDa. The insights obtained in this work provide valuable guidance that should facilitate future discovery of new complex self-replicating molecules. They may also assist in the development of new self-synthesizing materials, where self-assembly drives the synthesis of the very molecules that self-assemble. To illustrate the potential of this concept, the present system enables access to self-assembling materials made from self-synthesizing macrocycles with tunable ring size ranging from trimers to octamers.
Co-reporter:Sijbren Otto
Chemical Science 2013 vol. 4(Issue 7) pp:2953-2959
Publication Date(Web):09 May 2013
DOI:10.1039/C3SC50740H
Understanding hydrophobic interactions requires a molecular-level picture of how water molecules adjust to the introduction of a nonpolar solute. New insights into the latter process are derived from the observation that the Gibbs energies of solvation of the noble gases and linear alkanes by a wide range of solvents, including water, correlate well with linear combinations of internal pressure (Pi) and cohesive energy density (ced) of the solvent. Pi and ced are empirical solvent parameters that quantify two different aspects of solvent cohesion: the former reflects the cost of creating a cavity by a subtle rearrangement of solvent molecules, whereas the latter captures the cost of creating a cavity with complete disruption of solvent–solvent interactions. For the solvation of smaller solutes the internal pressure is the dominant parameter, while for larger solutes the ced becomes more important. The intriguing observation that the solubility of alkanes in water decreases with increasing chain length, whereas the solubility of noble gases increases with increasing size, can be understood by considering the different relative influences of the ced and Pi on the solvation processes of both classes of compounds. Also the solvation enthalpy, but not the entropy, correlates with linear combinations of solvent ced and Pi, albeit poorly, suggesting that the good correlations observed for the Gibbs energy are largely due to enthalpy, most likely that related to cavity formation.
Co-reporter:Vittorio Saggiomo;Yana R Hristova;R Frederick Ludlow
Journal of Systems Chemistry 2013 Volume 4( Issue 1) pp:
Publication Date(Web):2013 December
DOI:10.1186/1759-2208-4-2
The assessment of molecular similarity is a key step in the drug discovery process that has thus far relied almost exclusively on computational approaches. We now report an experimental method for similarity assessment based on dynamic combinatorial chemistry.In order to assess molecular similarity directly in solution, a dynamic molecular network was used in a two-step process. First, a clustering analysis was employed to determine the network’s innate discriminatory ability. A classification algorithm was then trained to enable the classification of unknowns. The dynamic molecular network used in this work was able to identify thin amines and ammonium ions in a set of 25 different, closely related molecules. After training, it was also able to classify unknown molecules based on the presence or absence of an ethylamine group.This is the first step in the development of molecular networks capable of predicting bioactivity based on an assessment of molecular similarity.
Co-reporter:Saleh Hamieh;Dr. Vittorio Saggiomo;Piotr Nowak;Elio Mattia;Dr. R. Frederick Ludlow; Sijbren Otto
Angewandte Chemie International Edition 2013 Volume 52( Issue 47) pp:12368-12372
Publication Date(Web):
DOI:10.1002/anie.201305744
Co-reporter:Saleh Hamieh;Dr. Vittorio Saggiomo;Piotr Nowak;Elio Mattia;Dr. R. Frederick Ludlow; Sijbren Otto
Angewandte Chemie 2013 Volume 125( Issue 47) pp:12594-12598
Publication Date(Web):
DOI:10.1002/ange.201305744
Co-reporter:Sijbren Otto
Accounts of Chemical Research 2012 Volume 45(Issue 12) pp:2200
Publication Date(Web):January 20, 2012
DOI:10.1021/ar200246j
Dynamic combinatorial libraries (DCLs) are molecular networks in which the network members exchange building blocks. The resulting product distribution is initially under thermodynamic control. Addition of a guest or template molecule tends to shift the equilibrium towards compounds that are receptors for the guest.This Account gives an overview of our work in this area. We have demonstrated the template-induced amplification of synthetic receptors, which has given rise to several high-affinity binders for cationic and anionic guests in highly competitive aqueous solution. The dynamic combinatorial approach allows for the identification of new receptors unlikely to be obtained through rational design. Receptor discovery is possible and more efficient in larger libraries. The dynamic combinatorial approach has the attractive characteristic of revealing interesting structures, such as catenanes, even when they are not specifically targeted. Using a transition-state analogue as a guest we can identify receptors with catalytic activity.Although DCLs were initially used with the reductionistic view of identifying new synthetic receptors or catalysts, it is becoming increasingly apparent that DCLs are also of interest in their own right. We performed detailed computational studies of the effect of templates on the product distributions of DCLs using DCLSim software. Template effects can be rationalized by considering the entire network: the system tends to maximize global host-guest binding energy. A data-fitting analysis of the response of the global position of the DCLs to the addition of the template using DCLFit software allowed us to disentangle individual host-guest binding constants. This powerful procedure eliminates the need for isolation and purification of the various individual receptors. Furthermore, local network binding events tend to propagate through the entire network and may be harnessed for transmitting and processing of information. We demonstrated this possibility in silico through a simple dynamic molecular network that can perform AND logic with input and output in the form of molecules.Not only are dynamic molecular networks responsive to externally added templates, but they also adjust to internal template effects, giving rise to self-replication. Recently we have started to explore scenarios where library members recognize copies of themselves, resulting in a self-assembly process that drives the synthesis of the very molecules that self-assemble. We have developed a system that shows unprecedented mechanosensitive self-replication behavior: depending on whether the solution is shaken, stirred or not agitated, we have obtained a hexameric replicator, a heptameric replicator or no replication, respectively. We rationalize this behavior through a mechanism in which replication is promoted by mechanically-induced fragmentation of self-assembled replicator fibers. These results represent a new mode of self-replication in which mechanical energy liberates replicators from a self-inhibited state. These systems may also be viewed as self-synthesizing, self-assembling materials. These materials can be captured photochemically, converting a free-flowing fiber solution into a hydrogel through photo-induced homolytic disulfide exchange.
Co-reporter:Saleh Hamieh, R. Frederick Ludlow, Olivier Perraud, Kevin R. West, Elio Mattia, and Sijbren Otto
Organic Letters 2012 Volume 14(Issue 21) pp:5404-5407
Publication Date(Web):October 12, 2012
DOI:10.1021/ol302260n
Designing synthetic receptors that bind biologically relevant guests in an aqueous solution remains a considerable challenge. We now report a new synthetic receptor for nicotine, selected from a dynamic combinatorial library, that binds this guest in water at neutral pH through a combination of hydrophobic and π–π interactions.
Co-reporter:Zaida Rodriguez-Docampo, Eugenia Eugenieva-Ilieva, Carsten Reyheller, Ana M. Belenguer, Stefan Kubik and Sijbren Otto
Chemical Communications 2011 vol. 47(Issue 35) pp:9798-9800
Publication Date(Web):02 Aug 2011
DOI:10.1039/C1CC13451E
Using dynamic combinatorial disulfide chemistry we have developed a new generation of neutral synthetic receptors for anions, based on a macrobicyclic peptide structure. These receptors show an exceptional affinity and selectivity for sulfate ions in aqueous solution [log Ka = 8.67 in 41 mol% (67 volume%) acetonitrile in water]. The high affinity depends on a delicate balance between rigidity and flexibility in the structure of the receptor.
Co-reporter:Rosemary A. R. Hunt and Sijbren Otto
Chemical Communications 2011 vol. 47(Issue 3) pp:847-858
Publication Date(Web):29 Nov 2010
DOI:10.1039/C0CC03759A
Combinatorial chemistry is a tool for selecting molecules with special properties. Dynamic combinatorial chemistry started off aiming to be just that. However, unlike ordinary combinatorial chemistry, the interconnectedness of dynamic libraries gives them an extra dimension. An understanding of these molecular networks at systems level is essential for their use as a selection tool and creates exciting new opportunities in systems chemistry. In this feature article we discuss selected examples and considerations related to the advanced exploitation of dynamic combinatorial libraries for their originally conceived purpose of identifying strong binding interactions. Also reviewed are examples illustrating a trend towards increasing complexity in terms of network behaviour and reversible chemistry. Finally, new applications of dynamic combinatorial chemistry in self-assembly, transport and self-replication are discussed.
Co-reporter:Jianwei Li;Dr. Jacqui M. A. Carnall;Dr. Marc C. A. Stuart ;Dr. Sijbren Otto
Angewandte Chemie 2011 Volume 123( Issue 36) pp:8534-8536
Publication Date(Web):
DOI:10.1002/ange.201103297
Co-reporter:Jianwei Li;Dr. Jacqui M. A. Carnall;Dr. Marc C. A. Stuart ;Dr. Sijbren Otto
Angewandte Chemie International Edition 2011 Volume 50( Issue 36) pp:8384-8386
Publication Date(Web):
DOI:10.1002/anie.201103297
Co-reporter:R. Frederick Ludlow
Journal of the American Chemical Society 2010 Volume 132(Issue 17) pp:5984-5986
Publication Date(Web):April 14, 2010
DOI:10.1021/ja1013689
Despite well over a decade of research on dynamic combinatorial chemistry it is still unclear whether large libraries are more or less likely to yield strong binders than small libraries. We have now addressed this question by simulating a set of libraries containing from 65 to 4828 compounds under a range of different building block and template concentrations. We investigated the effect of library size on (i) the probability of detecting any amplification; (ii) the probability of detecting the strongest binding library member present; and (iii) the binding affinity of the most amplified detectable library member. The results indicate bigger libraries are more likely to produce better binders and that the affinity of the best binders identified rises more rapidly than expected statistically on the basis of the number of screened library members. This implies that it should be advantageous to work with DCLs that are much larger than the vast majority reported thus far.
Co-reporter:Christopher A. Waudby;Marc C. A. Stuart;Ana M. Belenguer;Jacqui M. A. Carnall;Jérôme J.-P. Peyralans
Science 2010 Volume 327(Issue 5972) pp:1502-1506
Publication Date(Web):19 Mar 2010
DOI:10.1126/science.1182767
Co-reporter:Friederike M Mansfeld;Ho Yu Au-Yeung;Jeremy KM Sanders
Journal of Systems Chemistry 2010 Volume 1( Issue 1) pp:
Publication Date(Web):2010 December
DOI:10.1186/1759-2208-1-12
Molecular recognition at the environment provided by the phospholipid bilayer interface plays an important role in biology and is subject of intense investigation. Dynamic combinatorial chemistry is a powerful approach for exploring molecular recognition, but has thus far not been adapted for use in this special microenvironment.Thioester exchange was found to be a suitable reversible reaction to achieve rapid equilibration of dynamic combinatorial libraries at the egg phosphatidyl choline bilayer interface. Competing thioester hydrolysis can be minimised by judicial choice of the structure of the thioesters and the experimental conditions. Comparison of the library compositions in bulk solution with those in the presence of egg PC revealed that the latter show a bias towards the formation of library members rich in membrane-bound building blocks. This leads to a shift away from macrocyclic towards linear library members.The methodology to perform dynamic combinatorial chemistry at the phospholipid bilayer interface has been developed. The spatial confinement of building blocks to the membrane interface can shift the ring-chain equilibrium in favour of chain-like compounds. These results imply that interfaces may be used as a platform to direct systems to the formation of (informational) polymers under conditions where small macrocycles would dominate in the absence of interfacial confinement.
Co-reporter:Rosemary A. R. Hunt, R. Frederick Ludlow and Sijbren Otto
Organic Letters 2009 Volume 11(Issue 22) pp:5110-5113
Publication Date(Web):October 13, 2009
DOI:10.1021/ol901656x
Multicomponent chemical systems that exhibit a network of covalent and intermolecular interactions may produce interesting and often unexpected chemical or physical behavior. The formation of aggregates is a well-recognized example and presents a particular analytical challenge. We now report the development of a numerical fitting method capable of estimating equilibrium constants for the formation of aggregates from the product distribution of a dynamic combinatorial library containing self-recognizing library members.
Co-reporter:Friederike M. Mansfeld, Guoqiang Feng and Sijbren Otto
Organic & Biomolecular Chemistry 2009 vol. 7(Issue 20) pp:4289-4295
Publication Date(Web):14 Aug 2009
DOI:10.1039/B910197G
Few methods currently exist for controlling vesicle–vesicle adhesion. We now report a new system, based upon a multivalent guest and an amphiphilic receptor with a photo-isomerisable anchor that can be incorporated into lipid vesicles of different sizes. Large unilamellar vesicles containing our receptor were found to aggregate upon addition of the multivalent guest, independently of photoswitching between the two conformations of the anchor. However, for giant vesicles immobilised on a platinum wire, guest-mediated adhesion only occurred upon photo-isomerisation of the anchor. This behaviour was attributed to the dynamics introduced into the system through the conformational changes caused by irradiation.
Co-reporter:Zaida Rodriguez-Docampo and Sijbren Otto
Chemical Communications 2008 (Issue 42) pp:5301-5303
Publication Date(Web):11 Sep 2008
DOI:10.1039/B808725C
Hydrazone and disulfide exchange have been combined in a single system, but can be addressed independently: by adjusting the pH of the solution from acidic to mildly basic it is possible to switch from exclusively hydrazone exchange to exclusively disulfide exchange, while at intermediate pH both reactions occur simultaneously.
Co-reporter:Rosemary A. R. Hunt and Sijbren Otto
Chemical Communications 2011 - vol. 47(Issue 3) pp:NaN858-858
Publication Date(Web):2010/11/29
DOI:10.1039/C0CC03759A
Combinatorial chemistry is a tool for selecting molecules with special properties. Dynamic combinatorial chemistry started off aiming to be just that. However, unlike ordinary combinatorial chemistry, the interconnectedness of dynamic libraries gives them an extra dimension. An understanding of these molecular networks at systems level is essential for their use as a selection tool and creates exciting new opportunities in systems chemistry. In this feature article we discuss selected examples and considerations related to the advanced exploitation of dynamic combinatorial libraries for their originally conceived purpose of identifying strong binding interactions. Also reviewed are examples illustrating a trend towards increasing complexity in terms of network behaviour and reversible chemistry. Finally, new applications of dynamic combinatorial chemistry in self-assembly, transport and self-replication are discussed.
Co-reporter:Zaida Rodriguez-Docampo and Sijbren Otto
Chemical Communications 2008(Issue 42) pp:NaN5303-5303
Publication Date(Web):2008/09/11
DOI:10.1039/B808725C
Hydrazone and disulfide exchange have been combined in a single system, but can be addressed independently: by adjusting the pH of the solution from acidic to mildly basic it is possible to switch from exclusively hydrazone exchange to exclusively disulfide exchange, while at intermediate pH both reactions occur simultaneously.
Co-reporter:Jianwei Li, Piotr Nowak, Hugo Fanlo-Virgós and Sijbren Otto
Chemical Science (2010-Present) 2014 - vol. 5(Issue 12) pp:NaN4974-4974
Publication Date(Web):2014/08/20
DOI:10.1039/C4SC01998A
A new azobenzene-based dithiol building block was developed which, upon oxidation, forms predominantly a [2]catenane consisting of two interlocked trimers. In the presence of cyclodextrin templates a series of [2] and [3]catenanes was formed instead. We developed a method that enabled estimating the equilibrium constants for catenation in all of these systems. The formation of the [3]catenanes is either cooperative or anticooperative, depending on the nature of the cyclodextrin. Using molecular dynamics simulations, we linked positive and negative cooperativity to, respectively, burying and exposure of hydrophobic surfaces upon catenation. Our results underline the importance of directly quantifying noncovalent interactions within catenanes, as the corresponding pseudo-rotaxane model systems were found to be poor predictors of binding interactions in the actual catenane.
Co-reporter:Sijbren Otto
Chemical Science (2010-Present) 2013 - vol. 4(Issue 7) pp:NaN2959-2959
Publication Date(Web):2013/05/09
DOI:10.1039/C3SC50740H
Understanding hydrophobic interactions requires a molecular-level picture of how water molecules adjust to the introduction of a nonpolar solute. New insights into the latter process are derived from the observation that the Gibbs energies of solvation of the noble gases and linear alkanes by a wide range of solvents, including water, correlate well with linear combinations of internal pressure (Pi) and cohesive energy density (ced) of the solvent. Pi and ced are empirical solvent parameters that quantify two different aspects of solvent cohesion: the former reflects the cost of creating a cavity by a subtle rearrangement of solvent molecules, whereas the latter captures the cost of creating a cavity with complete disruption of solvent–solvent interactions. For the solvation of smaller solutes the internal pressure is the dominant parameter, while for larger solutes the ced becomes more important. The intriguing observation that the solubility of alkanes in water decreases with increasing chain length, whereas the solubility of noble gases increases with increasing size, can be understood by considering the different relative influences of the ced and Pi on the solvation processes of both classes of compounds. Also the solvation enthalpy, but not the entropy, correlates with linear combinations of solvent ced and Pi, albeit poorly, suggesting that the good correlations observed for the Gibbs energy are largely due to enthalpy, most likely that related to cavity formation.
Co-reporter:Friederike M. Mansfeld, Guoqiang Feng and Sijbren Otto
Organic & Biomolecular Chemistry 2009 - vol. 7(Issue 20) pp:NaN4295-4295
Publication Date(Web):2009/08/14
DOI:10.1039/B910197G
Few methods currently exist for controlling vesicle–vesicle adhesion. We now report a new system, based upon a multivalent guest and an amphiphilic receptor with a photo-isomerisable anchor that can be incorporated into lipid vesicles of different sizes. Large unilamellar vesicles containing our receptor were found to aggregate upon addition of the multivalent guest, independently of photoswitching between the two conformations of the anchor. However, for giant vesicles immobilised on a platinum wire, guest-mediated adhesion only occurred upon photo-isomerisation of the anchor. This behaviour was attributed to the dynamics introduced into the system through the conformational changes caused by irradiation.
Co-reporter:Zaida Rodriguez-Docampo, Eugenia Eugenieva-Ilieva, Carsten Reyheller, Ana M. Belenguer, Stefan Kubik and Sijbren Otto
Chemical Communications 2011 - vol. 47(Issue 35) pp:NaN9800-9800
Publication Date(Web):2011/08/02
DOI:10.1039/C1CC13451E
Using dynamic combinatorial disulfide chemistry we have developed a new generation of neutral synthetic receptors for anions, based on a macrobicyclic peptide structure. These receptors show an exceptional affinity and selectivity for sulfate ions in aqueous solution [log Ka = 8.67 in 41 mol% (67 volume%) acetonitrile in water]. The high affinity depends on a delicate balance between rigidity and flexibility in the structure of the receptor.
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![ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate](http://img.cochemist.com/ccimg/53600/53588-99-1_b.png)
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![TRICYCLO[3.3.1.13,7]DECAN-1-AMINIUM, N,N,N-TRIMETHYL-](http://img.cochemist.com/ccimg/46300/46244-96-6_b.png)
![Tricyclo[3.3.1.13,7]decan-1-aminium, N,N,N-trimethyl-, iodide](http://img.cochemist.com/ccimg/3800/3717-61-1.png)
![Tricyclo[3.3.1.13,7]decan-1-aminium, N,N,N-trimethyl-, iodide](http://img.cochemist.com/ccimg/3800/3717-61-1_b.png)
