Sijbren Otto

Mechanosensitive Self-Replication Driven by Self-Organization

At Sixes and Sevens Molecular synthesis and macroscopic aggregation have often been regarded as entirely separate processes. From the researchers standpoint, once reagents have been mixed, synthesis is largely passive, whereas processes such as crystallization can be more actively manipulated. Carnall et al. (p. 1502) characterized an unusual system in which the formation of aggregated cyclic macromolecules (macrocycles) from small peptide-based building blocks was governed by intimately interdependent factors ranging from the scale of covalent bond formation all the way to micron scale fiber growth. As the macrocycles stacked against one another to form the fibers, they remained loosely bonded enough internally to incorporate or expel individual building blocks. Varying the type of mechanical force applied to the growing fibers (either through shaking or stirring the solution), alternately favored formation of either 6-membered or 7-membered covalent macrocycles. The type of mechanical agitation applied to a solution influences which of two molecular products dominate. Self-replicating molecules are likely to have played an important role in the origin of life, and a small number of fully synthetic self-replicators have already been described. Yet it remains an open question which factors most effectively bias the replication toward the far-from-equilibrium distributions characterizing even simple organisms. We report here two self-replicating peptide-derived macrocycles that emerge from a small dynamic combinatorial library and compete for a common feedstock. Replication is driven by nanostructure formation, resulting from the assembly of the peptides into fibers held together by β sheets. Which of the two replicators becomes dominant is influenced by whether the sample is shaken or stirred. These results establish that mechanical forces can act as a selection pressure in the competition between replicators and can determine the outcome of a covalent synthesis.

Supramolecular systems chemistry

The field of supramolecular chemistry focuses on the non-covalent interactions between molecules that give rise to molecular recognition and self-assembly processes. Since most non-covalent interactions are relatively weak and form and break without significant activation barriers, many supramolecular systems are under thermodynamic control. Hence, traditionally, supramolecular chemistry has focused predominantly on systems at equilibrium. However, more recently, self-assembly processes that are governed by kinetics, where the outcome of the assembly process is dictated by the assembly pathway rather than the free energy of the final assembled state, are becoming topical. Within the kinetic regime it is possible to distinguish between systems that reside in a kinetic trap and systems that are far from equilibrium and require a continuous supply of energy to maintain a stationary state. In particular, the latter systems have vast functional potential, as they allow, in principle, for more elaborate structural and functional diversity of self-assembled systems - indeed, life is a prime example of a far-from-equilibrium system. In this Review, we compare the different thermodynamic regimes using some selected examples and discuss some of the challenges that need to be addressed when developing new functional supramolecular systems.

Dynamic Combinatorial Libraries: From Exploring Molecular Recognition to Systems Chemistry

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.

Reversible Covalent Chemistry in Drug Delivery

The targeting of drugs specifically to their sites of action is an important strategy for increasing drug efficacy. Chemists have come up with many elegant schemes that aim to convert drugs into magic bullets. This review focuses on the chemistry that underlies these schemes, with particular emphasis on two types of cleavable covalent bonds that are frequently used to link drugs to their various carriers: disulfide bonds and hydrazone bonds. These linkages have been used to release drugs under specific conditions; in the case of disulfides, cleavage is triggered by the mildly reducing environment found in intracellular fluids, and in the case of hydrazones, the acidic conditions that prevail in endosomes cause release of the drug. The applications of these chemistries in drug delivery are reviewed.

Diels-Alder reactions in water*

This review illustrates how water, as an environmentally friendly solvent, can have significant additional benefits when it is used as a solvent for the Diels_Alder reaction. The mechanism by which the unique properties of water enhance the rate and selectivity are discussed. Also, possibilities for the achievement of further increases in rate and enantioselectivity of aqueous Diels_Alder reactions through Lewis-acid and micellar catalysis are reviewed.

Lewis acid catalysis of a Diels-Alder reaction in water

Here we report the first detailed study of a Diels-Alder (DA) reaction that is catalyzed by Lewis acids in water. The effect of Co2+, Ni2+, Cu2+ and Zn2+ ions as Lewis acid catalysts on the rate and endo-exo selectivity of the DA reaction between the bidentate dienophiles 3-phenyl-1-(2-pyridyl)-2-propen-1-ones (1a-e) and cyclo-pentadiene (2) in water has been studied. Relative to the uncatalyzed reaction in acetonitrile, catalysis by 0.010 M CU(NO3)(2) in water accelerates the reaction by a factor of 79 300. The kinetics of the catalyzed reaction were analyzed in terms of equilibrium constants for complexation of the Lewis acid with 1a-e and rate constants for the reaction of the resulting complexes with 2. The rate enhancement imposed upon the uncatalyzed DA reaction of substrates 1 with 2 by water is much more pronounced than that for the catalyzed reaction. The increase of the endo-exo selectivity induced by water in the uncatalyzed process is completely absent for the Lewis acid catalyzed reaction. The modest solvent and substituent effects observed for the catalyzed reaction indicate that the change in charge separation during the activation process is not larger than the corresponding change For the uncatalyzed reaction.

Dynamic combinatorial chemistry

A combinatorial library that responds to its target by increasing the concentration of strong binders at the expense of weak binders sounds ideal. Dynamic combinatorial chemistry has the potential to achieve exactly this. In this review, we will highlight the unique features that distinguish dynamic combinatorial chemistry from traditional combinatorial chemistry, and that could make a useful addition to the set of combinatorial techniques used in drug discovery.

Recent developments in dynamic combinatorial chemistry

Generating combinatorial libraries under equilibrium conditions has the important advantage that the libraries are adaptive (i.e. they can respond to exterior influences in the form of molecular recognition events). Thus, a ligand will direct and amplify the formation of its ideal receptor and vice versa. Proof of principle of this approach has been established using small libraries showing highly efficient amplification of selected receptors. The approach has recently been extended to address folding of macromolecules, including peptides.

Dynamic Molecular Networks : From Synthetic Receptors to Self-Replicators

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.

Orthogonal or simultaneous use of disulfide and hydrazone exchange in dynamic covalent chemistry in aqueous solution

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.