Unsupervised Data-Driven Reconstruction of Molecular Motifs in Simple to Complex Dynamic Micelles.

The reshuffling mobility of molecular building blocks in self-assembled micelles is a key determinant of many their interesting properties, from emerging morphologies and surface compartmentalization, to dynamic reconfigurability and stimuli-responsiveness. However, the microscopic details of such complex structural dynamics are typically nontrivial to elucidate, especially in multicomponent assemblies. Here we show a machine-learning approach that allows us to reconstruct the structural and dynamic complexity of mono- and bicomponent surfactant micelles from high-dimensional data extracted from equilibrium molecular dynamics simulations. Unsupervised clustering of smooth overlap of atomic position (SOAP) data enables us to identify, in a set of multicomponent surfactant micelles, the dominant local molecular environments that emerge within them and to retrace their dynamics, in terms of exchange probabilities and transition pathways of the constituent building blocks. Tested on a variety of micelles differing in size and in the chemical nature of the constitutive self-assembling units, this approach effectively recognizes the molecular motifs populating them in an exquisitely agnostic and unsupervised way, and allows correlating them to their composition in terms of constitutive surfactant species.

Short peptide-based cross-ß amyloids exploit dual residues for phosphoesterase like activity.

Herein, we report that short peptides are capable of exploiting their anti-parallel registry to access cross-ß stacks to expose more than one catalytic residue, exhibiting the traits of advanced binding pockets of enzymes. Binding pockets decorated with more than one catalytic residue facilitate substrate binding and process kinetically unfavourable chemical transformations. The solvent-exposed guanidinium and imidazole moieties on the cross-ß microphases synergistically bind to polarise and hydrolyse diverse kinetically stable model substrates of nucleases and phosphatase. Mutation of either histidine or arginine results in a drastic decline in the rate of hydrolysis. These results not only support the argument of short amyloid peptides as the earliest protein folds but also suggest their interactions with nucleic acid congeners, foreshadowing the mutualistic biopolymer relationships that fueled the chemical emergence of life.

Nonequilibrium Catalytic Supramolecular Assemblies of Melamine- and Imidazole-Based Dynamic Building Blocks.

The development of synthetic nonequilibrium systems has gathered increasing attention due to their potential to illustrate the dynamic, complex, and emergent traits of biological systems. Simple building blocks capable of interacting via dynamic covalent chemistry and physical assembly in a reaction network under nonequilibrium conditions can contribute to our understanding of complex systems of life and its origin. Herein, we have demonstrated the nonequilibrium generation of catalytic supramolecular assemblies from simple heterocycle melamine driven by a thermodynamically activated ester. Utilizing a reversible covalent linkage, an imidazole moiety was recruited by the assemblies to access a catalytic transient state that dissipated energy via accelerated hydrolysis of the activated ester. The nonequilibrium assemblies were further capable of temporally binding to a hydrophobic guest to modulate its photophysical properties. Notably, the presence of an exogenous aromatic base augmented the lifetime of the catalytic microphases, reflecting their higher kinetic stability.

Substrate induced generation of transient self-assembled catalytic systems.

Living matter is sustained under non-equilibrium conditions via continuous expense of energy which is coordinated by complex organized events. Spatiotemporal control over exquisite functions arises from chemical complexity under non-equilibrium conditions. For instance, extant biology often uses substrate binding events to access temporally stable protein conformations which show acceleration of catalytic rates to subsequently degrade the substrate. Furthermore, thermodynamically activated but kinetically stable esters (GTP) induce the change of conformation of cytoskeleton proteins (microtubules) which leads to rapid polymerization and triggers an augmentation of catalytic rates to subsequently degrade the ester. Importantly, high-energy assemblies composed of non-activated building blocks (GDP-tubulin) are accessed utilizing the energy dissipated from the catalytic conversion of GTP to GDP from the assembled state. Notably, some experimental studies with simple self-assembled systems have elegantly mimicked the phenomena of substrate induced transient generation of catalytic conformations. Through this review, we endeavour to highlight those select studies which have used simple building blocks to demonstrate substrate induced self-assemblies that subsequently show rate acceleration to convert the substrate into waste. The concept of substrate induced self-assembly of building blocks and rate acceleration from the assembled state has the potential to play a predominant role in the preparation of non-equilibrium systems. The design strategies covered in this review can inspire the possibilities of accessing high energy self-assembled structures that are seen in living systems.

Cross-ß amyloid nanotubes for hydrolase-peroxidase cascade reactions.

Herein, we report the catalytic potential of short peptide based cross-ß amyloid nanotubes with surface exposed histidine capable of binding hemin and showing facile cascade reactions, playing the dual roles of hydrolases and peroxidases, two of the most important classes of enzymes in extant biology. The activity of these simple systems exceeded those of modern and larger proteins like cytochrome C and hemoglobin. Further, evidence suggested that these self-assembled nanotubes foreshadow the process of intermediate channeling, a feature seen in the case of advanced enzymes.

Aldolase Cascade Facilitated by Self-Assembled Nanotubes from Short Peptide Amphiphiles.

Early evolution benefited from a complex network of reactions involving multiple C-C bond forming and breaking events that were critical for primitive metabolism. Nature gradually chose highly evolved and complex enzymes such as lyases to efficiently facilitate C-C bond formation and cleavage with remarkable substrate selectivity. Reported here is a lipidated short peptide which accesses a homogenous nanotubular morphology to efficiently catalyze C-C bond cleavage and formation. This system shows morphology-dependent catalytic rates, suggesting the formation of a binding pocket and registered enhancements in the presence of the hydrogen-bond donor tyrosine, which is exploited by extant aldolases. These assemblies showed excellent substrate selectivity and templated the formation of a specific adduct from a pool of possible adducts. The ability to catalyze metabolically relevant cascade transformations suggests the importance of such systems in early evolution.

Designed Negative Feedback from Transiently Formed Catalytic Nanostructures.

Highly dynamic and complex systems of microtubules undergo a substrate-induced change of conformation that leads to polymerization. Owing to the augmented catalytic potential at the polymerized state, rapid hydrolysis of the substrate is observed, leading to catastrophe, thus realizing the out-of-equilibrium state. A simple synthetic mimic of these dynamic natural systems is presented, where similar substrate induced conformational change is observed and a transient helical morphology is accessed. Further, augmented catalytic potential of these helical nanostructures leads to rapid hydrolysis of the substrate providing negative feedback on the stability of the nanostructures and realization of an out-of-equilibrium state. This simple system, made from amino acid functionalized lipids, demonstrates a substrate-induced self-assembled state, where the fuel-to-waste conversion leads to the temporal presence of helical nanostructures.