Proximity-enhanced cysteine-histidine crosslinking for elucidating intrinsically disordered and other protein complexes.

Disordered proteins and domains are ubiquitous throughout the proteome of human cell types, yet the biomolecular sciences lack effective tool compounds and chemical strategies to study this class of proteins. In this context, we introduce a novel covalent tool compound approach that combines proximity-enhanced crosslinking with histidine trapping. Utilizing a maleimide-cyclohexenone crosslinker for efficient cysteine-histidine crosslinking, we elucidated the mechanism of this dual-reactive tool compound class.

Straightforward model construction and analysis of multicomponent biomolecular systems in equilibrium.

Mathematical modelling of molecular systems can be extremely helpful in elucidating complex phenomena in (bio)chemistry. However, equilibrium conditions in systems consisting of more than two components, such as for molecular glues bound to two proteins, can typically not be analytically determined without assumptions and (semi-)numerical models are not trivial to derive by the non-expert. Here we present a framework for equilibrium models, geared towards molecular glues and other contemporary multicomponent chemical biology challenges.

Unequal Perylene Diimide Twins in a Quadruple Assembly.

Natural light-harvesting (LH) systems can divide identical dyes into unequal aggregate states, thereby achieving intelligent "allocation of labor". From a synthetic point of view, the construction of such kinds of unequal and integrated systems without the help of proteinaceous scaffolding is challenging. Here, we show that four octatetrayne-bridged ortho-perylene diimide (PDI) dyads (POPs) self-assemble into a quadruple assembly (POP) both in solution and in the solid state.

On the role of membrane embedding, protein rigidity and transmembrane length in lipid membrane fusion.

The fusion of biological membranes is ubiquitous in natural processes like exo- and endocytosis, intracellular trafficking and viral entry. Membrane fusion is also utilized in artificial biomimetic fusion systems, for drug delivery. Both the natural and the biomimetic fusion systems rely on a wide range of (artificial) proteins mediating the fusion process.

Designed Asymmetric Protein Assembly on a Symmetric Scaffold.

Cellular signaling is regulated by the assembly of proteins into higher-order complexes. Bottom-up creation of synthetic protein assemblies, especially asymmetric complexes, is highly challenging. Presented here is the design and implementation of asymmetric assembly of a ternary protein complex facilitated by Rosetta modeling and thermodynamic analysis.

Proximity-induced caspase-9 activation on a DNA origami-based synthetic apoptosome.

Living cells regulate key cellular processes by spatial organisation of catalytically active proteins in higher-order signalling complexes. These act as organising centres to facilitate proximity-induced activation and inhibition of multiple intrinsically weakly associating signalling components, which makes elucidation of the underlying protein-protein interactions challenging. Here we show that DNA origami nanostructures provide a programmable molecular platform for the systematic analysis of signalling proteins by engineering a synthetic DNA origami-based version of the apoptosome, a multi-protein complex that regulates apoptosis by co-localizing multiple caspase-9 monomers.

Photodynamic Control of the Chain Length in Supramolecular Polymers: Switching an Intercalator into a Chain Capper.

Supramolecular systems are intrinsically dynamic and sensitive to changes in molecular structure and external conditions. Because of these unique properties, strategies to control polymer length, composition, comonomer sequence, and morphology have to be developed for sufficient control over supramolecular copolymerizations. We designed photoresponsive, mono acyl hydrazone functionalized benzene-1,3,5-tricarboxamide () monomers that play a dual role in the coassembly with achiral alkyl BTAs ().

Mass-Balance Models for Scrutinizing Supramolecular (Co)polymerizations in Thermodynamic Equilibrium.

Recent years have witnessed increasing attention on supramolecular polymerization, i.e., the formation of one-dimensional aggregates in which the monomeric units bind together via reversible and usually highly directional non-covalent interactions.

Tuning the Length of Cooperative Supramolecular Polymers under Thermodynamic Control.

In the field of supramolecular (co)polymerizations, the ability to predict and control the composition and length of the supramolecular (co)polymers is a topic of great interest. In this work, we elucidate the mechanism that controls the polymer length in a two-component cooperative supramolecular polymerization and unveil the role of the second component in the system. We focus on the supramolecular copolymerization between two derivatives of benzene-1,3,5-tricarboxamide (BTA) monomers: and .

Detailed Approach to Investigate Thermodynamically Controlled Supramolecular Copolymerizations.

Elucidating the microstructure of supramolecular copolymers remains challenging, despite the progress in the field of supramolecular polymers. In this work, we present a detailed approach to investigate supramolecular copolymerizations under thermodynamic control. Our approach provides insight into the interactions of different types of monomers and hereby allows elucidating the microstructure of copolymers.

Counterion-Dependent Mechanisms of DNA Origami Nanostructure Stabilization Revealed by Atomistic Molecular Simulation.

The DNA origami technique has proven to have tremendous potential for therapeutic and diagnostic applications like drug delivery, but the relatively low concentrations of cations in physiological fluids cause destabilization and degradation of DNA origami constructs preventing applications. To reveal the mechanisms behind DNA origami stabilization by cations, we performed atomistic molecular dynamics simulations of a DNA origami rectangle in aqueous solvent with varying concentrations of magnesium and sodium as well as polyamines like oligolysine and spermine. We explored the binding of these ions to DNA origami in detail and found that the mechanism of stabilization differs between ion types considerably.

Equilibrium Model for Supramolecular Copolymerizations.

The coassembly of different building blocks into supramolecular copolymers provides a promising avenue to control their properties and to thereby expand the potential of supramolecular polymers in applications. However, contrary to covalent copolymerization which nowadays can be well controlled, the control over sequence, polymer length, and morphology in supramolecular copolymers is to date less developed, and their structures are more determined by the delicate balance in binding free energies between the distinct building blocks than by kinetics. Consequently, to rationalize the structures of supramolecular copolymers, a thorough understanding of their thermodynamic behavior is needed.

Unexpectedly Strong Chiral Amplification of Chiral/Achiral and Chiral/Chiral Copolymers of Biphenylylacetylenes and Further Enhancement/Inversion and Memory of the Macromolecular Helicity.

We report an unexpectedly strong amplification of the macromolecular helicity in dynamic helical copolymers of chiral/achiral and chiral/chiral ( R/ S) biphenylylacetylenes in which the chiral residues are remote from the biphenyl pendants and further from the main chains. The copolymers consisting of 20 mol % chiral monomers and chiral monomers of 20% enantiomeric excess (ee) showed a full induced circular dichroism as intense as that of the chiral homopolymer. In contrast, an analogous poly(phenylacetylene) bearing the identical chiral residue (100% ee) showed no circular dichroism in the polymer backbone, indicating the critical role of the biphenyl moieties in the observed high chiral amplification.

Multivalency in a Dendritic Host-Guest System.

Multivalency is an important instrument in the supramolecular chemistry toolkit for the creation of strong specific interactions. In this paper we investigate the multivalency effect in a dendritic host-guest system using molecular dynamics simulations. Specifically, we consider urea-adamantyl decorated poly(propyleneimine) dendrimers that together with compatible mono-, bi-, and tetravalent ureidoacetic acid guests can form dynamic patchy nanoparticles.

Competing Interactions in Hierarchical Porphyrin Self-Assembly Introduce Robustness in Pathway Complexity.

Pathway complexity in supramolecular polymerization has recently sparked interest as a method to generate complex material behavior. The response of these systems relies on the existence of a metastable, kinetically trapped state. In this work, we show that strong switch-like behavior in supramolecular polymers can also be achieved through the introduction of competing aggregation pathways.

Supramolecular Block Copolymers under Thermodynamic Control.

Supramolecular block copolymers are becoming attractive materials in nascent optoelectronic and catalytic technologies. However, their dynamic nature precludes the straightforward tuning and analysis of the polymer's structure. Here we report the elucidation on the microstructure of triarylamine triamide-based supramolecular block copolymers through a comprehensive battery of spectroscopic, theoretical, and super-resolution microscopic techniques.

Elucidation of the origin of chiral amplification in discrete molecular polyhedra.

Chiral amplification in molecular self-assembly has profound impact on the recognition and separation of chiroptical materials, biomolecules, and pharmaceuticals. An understanding of how to control this phenomenon is nonetheless restricted by the structural complexity in multicomponent self-assembling systems. Here, we create chiral octahedra incorporating a combination of chiral and achiral vertices and show that their discrete nature makes these octahedra an ideal platform for in-depth investigation of chiral transfer.

Photoisomerization induced scission of rod-like micelles unravelled with multiscale modeling.

Hypothesis: In photorheological fluids, subtle molecular changes caused by light lead to abrupt macroscopic alterations. Upon UV irradiation of an aqueous cetyltrimethylammonium bromide (CTAB) and trans-ortho-methoxycinnamic acid (trans-OMCA) solution, for instance, the viscosity drops over orders of magnitude. Multiscale modeling allows to elucidate the mechanisms behind these photorheological effects.

Supramolecular Copolymers: Structure and Composition Revealed by Theoretical Modeling.

Supramolecular copolymers, non-covalent analogues of synthetic copolymers, constitute a new and promising class of polymers. In contrast to their covalent counterparts, the details of their mechanism of formation, as well as the factors determining their composition and length, are still poorly understood. Here, the supramolecular copolymerization between two slightly structurally different benzene-1,3,5-tricarboxamide (BTA) monomers functionalized with either oligodimethylsiloxane (oDMSi) or alkyl side chains is unraveled by combining experimental and theoretical approaches.

Non-equilibrium supramolecular polymerization.

Supramolecular polymerization has been traditionally focused on the thermodynamic equilibrium state, where one-dimensional assemblies reside at the global minimum of the Gibbs free energy. The pathway and rate to reach the equilibrium state are irrelevant, and the resulting assemblies remain unchanged over time. In the past decade, the focus has shifted to kinetically trapped (non-dissipative non-equilibrium) structures that heavily depend on the method of preparation (i.

Fragmentation and Coagulation in Supramolecular (Co)polymerization Kinetics.

The self-assembly of molecular building blocks into one-dimensional supramolecular architectures has opened up new frontiers in materials science. Due to the noncovalent interactions between the monomeric units, these architectures are intrinsically dynamic, and understanding their kinetic driving forces is key to rationally programming their morphology and function. To understand the self-assembly dynamics of supramolecular polymerizations (SP), kinetic models based on aggregate growth by sequential monomer association and dissociation have been analyzed.

Coarse-grained simulations of poly(propylene imine) dendrimers in solution.

The behavior of poly(propylene imine) (PPI) dendrimers in concentrated solutions has been investigated using molecular dynamics simulations containing up to a thousand PPI dendrimers of generation 4 or 5 in explicit water. To deal with large system sizes and time scales required to study the solutions over a wide range of dendrimer concentrations, a previously published coarse-grained model was applied. Simulation results on the radius of gyration, structure factor, intermolecular spacing, dendrimer interpenetration, and water penetration are compared with available experimental data, providing a clear concentration dependent molecular picture of PPI dendrimers.

Kinetic Analysis as a Tool to Distinguish Pathway Complexity in Molecular Assembly: An Unexpected Outcome of Structures in Competition.

While the sensitive dependence of the functional characteristics of self-assembled nanofibers on the molecular structure of their building blocks is well-known, the crucial influence of the dynamics of the assembly process is often overlooked. For natural protein-based fibrils, various aggregation mechanisms have been demonstrated, from simple primary nucleation to secondary nucleation and off-pathway aggregation. Similar pathway complexity has recently been described in synthetic supramolecular polymers and has been shown to be intimately linked to their morphology.

Programmable chemical reaction networks: emulating regulatory functions in living cells using a bottom-up approach.

Living cells are able to produce a wide variety of biological responses when subjected to biochemical stimuli. It has become apparent that these biological responses are regulated by complex chemical reaction networks (CRNs). Unravelling the function of these circuits is a key topic of both systems biology and synthetic biology.