In silico characterization of the psilocybin biosynthesis pathway.

Nearly all mushrooms of the Psilocybe genus contain the natural product psilocybin, which is a psychoactive alkaloid derived from l-tryptophan. Considering their use in ancient times, as well as their psychedelic properties, these mushrooms have re-emerged with psychotherapeutic potential for treating depression, which has triggered increased pharmaceutical interest. However, the psilocybin biosynthesis pathway was only recently defined and, as such, little exists in the way of structural data. Accordingly, the aim of this study was to structurally characterize this pathway by generating homology models for the four Psilocybe cubensis enzymes involved in psilocybin biosynthesis (PsiD, a decarboxylase; PsiH, a monooxygenase; PsiK, a phosphotransferase; PsiM, a methyltransferase). Following initial model generation and alignment with the identified structural templates, repeated refinement of the models was carried out using secondary structure prediction, geometry evaluation, energy minimization, and molecular dynamics simulations in water. The final models were then evaluated using molecular docking interactions with their substrates, i.e., psilocybin precursors (l-tryptophan, tryptamine, 4-hydroxytryptamine, and norbaeocystin/baeocystin), all of which generated feasible binding modes for the expected biotransformation. Further plausibility of the psilocybin → aeruginascin, 4-hydroxytryptamine → norpsilocin, and tryptamine → N,N-dimethyltryptamine conversions, all mediated by the generated model for PsiM, suggests valid routes of formation for these key secondary metabolites. The structural characterization of these enzymes and their binding modes which emerged from this study can lead to a better understanding of psilocybin synthesis, thereby paving the way for the development of novel substrates and selective inhibitors, as well as improved biotechnological manipulation and production of psilocybin in vitro.

In Silico Design and SAR Study of Dibenzyl Trisulfide Analogues for Improved CYP1A1 Inhibition.

Dibenzyl trisulfide (DTS) is a natural compound with potential cancer-preventive properties occurring in Petiveria alliacea L., an ethnomedicinal plant native to the Americas. Previous studies revealed its inhibitory activity toward cytochrome P450 (CYP)1 enzymes, key in the activation of environmental pollutants. Accordingly, the aim of this study was to design novel DTS analogues, aimed at improving not only inhibitory activity, but also specificity toward CYP1A1. This was achieved by targeting interactions with CYP1A1 residues of identified importance. Three-dimensional structures for the novel analogues were subjected to molecular docking with several CYP isoforms, before being ranked in terms of binding affinity to CYP1A1. With three hydrogen bond donors, two hydrogen bond acceptors, a molecular mass of 361 Da, and a log P of 3.72, the most promising DTS analogue obeys Lipinski's rule of five. Following synthesis and in vitro validation of its CYP1A1-inhibitory properties, this compound may be useful in future cancer-preventive approaches.

Real-space origin of topological band gaps, localization, and reentrant phase transitions in gyroscopic metamaterials.

Lattices of interacting gyroscopes naturally support band gaps and topologically protected wave transport along material boundaries. Recently the authors and their collaborators found that amorphous arrangements of such coupled gyroscopes also support nontrivial topological phases. In contrast to periodic systems, for which there is a comprehensive understanding and predictive framework for band gaps and band topology, the theory of spectral gaps and topology for amorphous materials remains less developed. Here we use experiments, numerics, and analytic tools to address the relationship between local interactions and nontrivial topology. We begin with a derivation of the equations of motion within the framework of symplectic mechanics. We then present a general method for predicting whether a gap exists and for approximating the Chern number using only local features of a network, bypassing the costly diagonalization of the system's dynamical matrix. Finally we study how strong disorder interacts with band topology in gyroscopic metamaterials and find that amorphous gyroscopic Chern insulators exhibit similar critical behavior to periodic lattices. Our experiments and simulations additionally reveal a topological Anderson insulation transition, wherein disorder drives a trivial phase into a topological one.

Transmembrane transport in inorganic colloidal cell-mimics.

A key aspect of living cells is their ability to harvest energy from the environment and use it to pump specific atomic and molecular species in and out of their system-typically against an unfavourable concentration gradient1. Active transport allows cells to store metabolic energy, extract waste and supply organelles with basic building blocks at the submicrometre scale. Unlike living cells, abiotic systems do not have the delicate biochemical machinery that can be specifically activated to precisely control biological matter2-5. Here we report the creation of microcapsules that can be brought out of equilibrium by simple global variables (illumination and pH), to capture, concentrate, store and deliver generic microscopic payloads. Borrowing no materials from biology, our design uses hollow colloids serving as spherical cell-membrane mimics, with a well-defined single micropore. Precisely tunable monodisperse capsules are the result of a synthetic self-inflation mechanism and can be produced in bulk quantities. Inside the hollow unit, a photoswitchable catalyst6 produces a chemical gradient that propagates to the exterior through the membrane's micropore and pumps target objects into the cell, acting as a phoretic tractor beam7. An entropic energy barrier8,9 brought about by the micropore's geometry retains the cargo even when the catalyst is switched off. Delivery is accomplished on demand by reversing the sign of the phoretic interaction. Our findings provide a blueprint for developing the next generation of smart materials, autonomous micromachinery and artificial cell-mimics.

Dibenzyl trisulfide binds to and competitively inhibits the cytochrome P450 1A1 active site without impacting the expression of the aryl hydrocarbon receptor.

The toxicological manifestation of many pollutants relies upon their binding to the aryl hydrocarbon receptor (AHR), and it follows a cascade of reactions culminating in an elevated expression of cytochrome P450 (CYP) 1 enzymes. CYP1A1 and CYP1B1 are associated with enhanced carcinogenesis when chronically exposed to certain polyaromatic hydrocarbons, and their inhibition may lead to chemoprevention. We evaluated dibenzyl trisulfide (DTS), expressed in the ethnomedical plant, Petiveria alliacea, for such potential chemoprevention. Using recombinant human CYP1A1 and CYP1B1 bactosomes on a fluorogenic assay, we first demonstrated that DTS moderately inhibited both enzymes with half maximal inhibitory concentration (IC50) values of 1.3 ± 0.3 and 1.7 ± 0.3 µM, respectively. Against CYP1A1, DTS was a reversible, competitive inhibitor with an apparent inhibitory constant (Ki) of 4.55 ± 0.37 µM. In silico molecular modeling showed that DTS binds with an affinity of -39.8 kJ·mol-1, situated inside the binding pocket, approximately 4.3 Å away from the heme group, exhibiting interactions with phenylalanine residue 123 (Phe-123), Phe-224, and Phe-258. Lastly, zebrafish (Danio rerio) embryos were exposed to 0.08-0.8 µM DTS from 24 to 96 h post fertilization (hpf) with the in vivo ethoxyresorufin-O-deethylase (EROD) assay, and, at 96 hpf, DTS significantly suppressed EROD CYP1A activity in a dose-dependent manner, with up to 60% suppression in the highest 0.8 µM exposure group. DTS had no impact on gene transcription levels for cyp1a and aryl hydrocarbon receptor 2 (ahr2). In co-exposure experiments, DTS suppressed CYP1A activity induced by both B[a]P and PCB-126, although these reductions were not significant. Taken together, these results demonstrate that DTS is a direct, reversible, competitive inhibitor of the carcinogen-activating CYP1A enzyme, binding in the active site pocket close to the heme site, and shows potential in chemoprevention.

Non-Hermitian Band Topology and Skin Modes in Active Elastic Media.

Solids built out of active components can exhibit nonreciprocal elastic coefficients that give rise to non-Hermitian wave phenomena. Here, we investigate non-Hermitian effects present at the boundary of two-dimensional active elastic media obeying two general assumptions: their microscopic forces conserve linear momentum and arise only from static deformations. Using continuum equations, we demonstrate the existence of the non-Hermitian skin effect in which the boundary hosts an extensive number of localized modes. Furthermore, lattice models reveal non-Hermitian topological transitions mediated by exceptional rings driven by the activity level of individual bonds.

Starting Flow Past an Airfoil and its Acquired Lift in a Superfluid.

We investigate superfluid flow around an airfoil accelerated to a finite velocity from rest. Using simulations of the Gross-Pitaevskii equation we find striking similarities to viscous flows: from production of starting vortices to convergence of airfoil circulation onto a quantized version of the Kutta-Joukowski circulation. We predict the number of quantized vortices nucleated by a given foil via a phenomenological argument. We further find stall-like behavior governed by airfoil speed, not angle of attack, as in classical flows. Finally we analyze the lift and drag acting on the airfoil.

Multiscale Modeling and Simulation Approaches to Lipid-Protein Interactions.

Lipid membranes play a crucial role in living systems by compartmentalizing biological processes and forming a barrier between these processes and the environment. Naturally, a large apparatus of biomolecules is responsible for construction, maintenance, transport, and degradation of these lipid barriers. Additional classes of biomolecules are tasked with transport of specific substances or transduction of signals from the environment across lipid membranes. In this article, we intend to describe a set of techniques that enable one to build accurate models of lipid systems and their associated proteins, and to simulate their dynamics over a variety of time and length scales. We discuss the methods and challenges that allow us to derive structural, mechanistic, and thermodynamic information from these models. We also show how these models have recently been applied in research to study some of the most complex lipid-protein systems to date, including bacterial and viral envelopes, neuronal membranes, and mammalian signaling systems.

Computational Prediction of Amino Acids Governing Protein-Membrane Interaction for the PIP3 Cell Signaling System.

Prediction and characterization of how transiently membrane-bound signaling proteins interact with the cell membrane is important for understanding and controlling cellular signal transduction networks. Existing computational methods rely on approximate descriptions of the components of the system or their interactions, and thus are unable to identify residue- or lipid-specific contributions. Our rotational interaction energy profiling method allows rapid evaluation of an electrostatically optimal orientation of a protein for membrane association, as well as the residues or lipid species responsible for its favorability. This enables prediction of which aspects of the protein-membrane interaction to target experimentally, and thus the development of testable hypotheses, as well as providing efficient seeding of molecular dynamics simulations to further characterize the protein-membrane interaction. We illustrate our method on two proteins of the PIP3 cell signaling system, PTEN and PI3Kα.

Self-organization in dipolar cube fluids constrained by competing anisotropies.

For magnetite spherical nanoparticles, the orientation of the dipole moment in the crystal does not affect the morphology of either zero field or field induced structures. For non-spherical particles however, an interplay between particle shape and direction of the magnetic moment can give rise to unusual behaviors, in particular when the moment is not aligned along a particle symmetry axis. Here we disclose for the first time the unique magnetic properties of hematite cubic particles and show the exact orientation of the cubes' dipole moment. Using a combination of experiments and computer simulations, we show that dipolar hematite cubes self-organize into dipolar chains with morphologies remarkably different from those of spheres, and demonstrate that the emergence of these structures is driven by competing anisotropic interactions caused by the particles' shape anisotropy and their fixed dipole moment. Furthermore, we have analytically identified a specific interplay between energy, and entropy at the microscopic level and found that an unorthodox entropic contribution mediates the organization of particles into the kinked nature of the dipolar chains.

Complete measurement of helicity and its dynamics in vortex tubes.

Helicity, a topological measure of the intertwining of vortices in a fluid flow, is a conserved quantity in inviscid fluids but can be dissipated by viscosity in real flows. Despite its relevance across a range of flows, helicity in real fluids remains poorly understood because the entire quantity is challenging to measure. We measured the total helicity of thin-core vortex tubes in water. For helical vortices that are stretched or compressed by a second vortex, we found conservation of total helicity. For an isolated helical vortex, we observed evolution toward and maintenance of a constant helicity state after the dissipation of twist helicity by viscosity. Our results show that helicity can remain constant even in a viscous fluid and provide an improved basis for understanding and manipulating helicity in real flows.

Fracture in sheets draped on curved surfaces.

Conforming materials to rigid substrates with Gaussian curvature-positive for spheres and negative for saddles-has proven a versatile tool to guide the self-assembly of defects such as scars, pleats, folds, blisters, and liquid crystal ripples. Here, we show how curvature can likewise be used to control material failure and guide the paths of cracks. In our experiments, and unlike in previous studies on cracked plates and shells, we constrained flat elastic sheets to adopt fixed curvature profiles. This constraint provides a geometric tool for controlling fracture behaviour: curvature can stimulate or suppress the growth of cracks and steer or arrest their propagation. A simple analytical model captures crack behaviour at the onset of propagation, while a two-dimensional phase-field model with an added curvature term successfully captures the crack's path. Because the curvature-induced stresses are independent of material parameters for isotropic, brittle media, our results apply across scales.

Spatiotemporal order and emergent edge currents in active spinner materials.

Collections of interacting, self-propelled particles have been extensively studied as minimal models of many living and synthetic systems from bird flocks to active colloids. However, the influence of active rotations in the absence of self-propulsion (i.e., spinning without walking) remains less explored. Here, we numerically and theoretically investigate the behavior of ensembles of self-spinning dimers. We find that geometric frustration of dimer rotation by interactions yields spatiotemporal order and active melting with no equilibrium counterparts. At low density, the spinning dimers self-assemble into a triangular lattice with their orientations phase-locked into spatially periodic phases. The phase-locked patterns form dynamical analogs of the ground states of various spin models, transitioning from the three-state Potts antiferromagnet at low densities to the striped herringbone phase of planar quadrupoles at higher densities. As the density is raised further, the competition between active rotations and interactions leads to melting of the active spinner crystal. Emergent edge currents, whose direction is set by the chirality of the active spinning, arise as a nonequilibrium signature of the transition to the active spinner liquid and vanish when the system eventually undergoes kinetic arrest at very high densities. Our findings may be realized in systems ranging from liquid crystal and colloidal experiments to tabletop realizations using macroscopic chiral grains.

Weaving Knotted Vector Fields with Tunable Helicity.

We present a general construction of divergence-free knotted vector fields from complex scalar fields, whose closed field lines encode many kinds of knots and links, including torus knots, their cables, the figure-8 knot, and its generalizations. As finite-energy physical fields, they represent initial states for fields such as the magnetic field in a plasma, or the vorticity field in a fluid. We give a systematic procedure for calculating the vector potential, starting from complex scalar functions with knotted zero filaments, thus enabling an explicit computation of the helicity of these knotted fields. The construction can be used to generate isolated knotted flux tubes, filled by knots encoded in the lines of the vector field. Lastly, we give examples of manifestly knotted vector fields with vanishing helicity. Our results provide building blocks for analytical models and simulations alike.

Topological mechanics of gyroscopic metamaterials.

Topological mechanical metamaterials are artificial structures whose unusual properties are protected very much like their electronic and optical counterparts. Here, we present an experimental and theoretical study of an active metamaterial--composed of coupled gyroscopes on a lattice--that breaks time-reversal symmetry. The vibrational spectrum displays a sonic gap populated by topologically protected edge modes that propagate in only one direction and are unaffected by disorder. We present a mathematical model that explains how the edge mode chirality can be switched via controlled distortions of the underlying lattice. This effect allows the direction of the edge current to be determined on demand. We demonstrate this functionality in experiment and envision applications of these edge modes to the design of one-way acoustic waveguides.

Shape-sensitive crystallization in colloidal superball fluids.

Guiding the self-assembly of materials by controlling the shape of the individual particle constituents is a powerful approach to material design. We show that colloidal silica superballs crystallize into canted phases in the presence of depletants. Some of these phases are consistent with the so-called "Λ1" lattice that was recently predicted as the densest packing of superdisks. As the size of the depletant is reduced, however, we observe a transition to a square phase. The differences in these entropically stabilized phases result from an interplay between the size of the depletants and the fine structure of the superball shape. We find qualitative agreement of our experimental results both with a phase diagram computed on the basis of the volume accessible to the depletants and with simulations. By using a mixture of depletants, one of which is thermosensitive, we induce solid-to-solid phase transitions between square and canted structures. The use of depletant size to leverage fine features of the shape of particles in driving their self-assembly demonstrates a general and powerful mechanism for engineering novel materials.

Soft epitaxy of nanocrystal superlattices.

Epitaxial heterostructures with precise registry between crystal layers play a key role in electronics and optoelectronics. In a close analogy, performance of nanocrystal (NC) based devices depends on the perfection of interfaces formed between NC layers. Here we systematically study the epitaxial growth of NC layers for the first time to enable the fabrication of coherent NC layers. NC epitaxy reveals an exceptional strain tolerance. It follows a universal island size scaling behaviour and shows a strain-driven transition from layer-by-layer to Stranski-Krastanov growth with non-trivial island height statistics. Kinetic bottlenecks play an important role in NC epitaxy, especially in the transition from sub-monolayer to multilayer coverage and the epitaxy of NCs with anisotropic shape. These findings provide a foundation for the rational design of epitaxial structures in a fundamentally and practically important size regime between atomic and microscopic systems.

Helicity conservation by flow across scales in reconnecting vortex links and knots.

The conjecture that helicity (or knottedness) is a fundamental conserved quantity has a rich history in fluid mechanics, but the nature of this conservation in the presence of dissipation has proven difficult to resolve. Making use of recent advances, we create vortex knots and links in viscous fluids and simulated superfluids and track their geometry through topology-changing reconnections. We find that the reassociation of vortex lines through a reconnection enables the transfer of helicity from links and knots to helical coils. This process is remarkably efficient, owing to the antiparallel orientation spontaneously adopted by the reconnecting vortices. Using a new method for quantifying the spatial helicity spectrum, we find that the reconnection process can be viewed as transferring helicity between scales, rather than dissipating it. We also infer the presence of geometric deformations that convert helical coils into even smaller scale twist, where it may ultimately be dissipated. Our results suggest that helicity conservation plays an important role in fluids and related fields, even in the presence of dissipation.

Tying knots in light fields.

We construct analytically, a new family of null solutions to Maxwell's equations in free space whose field lines encode all torus knots and links. The evolution of these null fields, analogous to a compressible flow along the Poynting vector that is shear free, preserves the topology of the knots and links. Our approach combines the construction of null fields with complex polynomials on S3. We examine and illustrate the geometry and evolution of the solutions, making manifest the structure of nested knotted tori filled by the field lines.