Limits of economy and fidelity for programmable assembly of size-controlled triply periodic polyhedra.

We propose and investigate an extension of the Caspar-Klug symmetry principles for viral capsid assembly to the programmable assembly of size-controlled triply periodic polyhedra, discrete variants of the Primitive, Diamond, and Gyroid cubic minimal surfaces. Inspired by a recent class of programmable DNA origami colloids, we demonstrate that the economy of design in these crystalline assemblies-in terms of the growth of the number of distinct particle species required with the increased size-scale (e.g., periodicity)-is comparable to viral shells. We further test the role of geometric specificity in these assemblies via dynamical assembly simulations, which show that conditions for simultaneously efficient and high-fidelity assembly require an intermediate degree of flexibility of local angles and lengths in programmed assembly. Off-target misassembly occurs via incorporation of a variant of disclination defects, generalized to the case of hyperbolic crystals. The possibility of these topological defects is a direct consequence of the very same symmetry principles that underlie the economical design, exposing a basic tradeoff between design economy and fidelity of programmable, size controlled assembly.

Multiscale Modeling of Hepatitis B Virus Capsid Assembly and Its Dimorphism.

Hepatitis B virus (HBV) is an endemic, chronic virus that leads to 800000 deaths per year. Central to the HBV lifecycle, the viral core has a protein capsid assembled from many copies of a single protein. The capsid protein adopts different (quasi-equivalent) conformations to form icosahedral capsids containing 180 or 240 proteins: T = 3 or T = 4, respectively, in Caspar-Klug nomenclature. HBV capsid assembly has become an important target for recently developed antivirals; nonetheless, the assembly pathways and mechanisms that control HBV dimorphism remain unclear. We describe computer simulations of the HBV assembly, using a coarse-grained model that has parameters learned from all-atom molecular dynamics simulations of a complete HBV capsid and yet is computationally tractable. Dynamical simulations with the resulting model reproduce experimental observations of HBV assembly pathways and products. By constructing Markov state models and employing transition path theory, we identify pathways leading to T = 3, T = 4, and other experimentally observed capsid morphologies. The analysis shows that capsid polymorphism is promoted by the low HBV capsid bending modulus, where the key factors controlling polymorphism are the conformational energy landscape and protein-protein binding affinities.

Polymorphic self-assembly of helical tubules is kinetically controlled.

In contrast to most self-assembling synthetic materials, which undergo unbounded growth, many biological self-assembly processes are self-limited. That is, the assembled structures have one or more finite dimensions that are much larger than the size scale of the individual monomers. In many such cases, the finite dimension is selected by a preferred curvature of the monomers, which leads to self-closure of the assembly. In this article, we study an example class of self-closing assemblies: cylindrical tubules that assemble from triangular monomers. By combining kinetic Monte Carlo simulations, free energy calculations, and simple theoretical models, we show that a range of programmable size scales can be targeted by controlling the intricate balance between the preferred curvature of the monomers and their interaction strengths. However, their assembly is kinetically controlled-the tubule morphology is essentially fixed shortly after closure, resulting in a distribution of tubule widths that is significantly broader than the equilibrium distribution. We develop a simple kinetic model based on this observation and the underlying free-energy landscape of assembling tubules that quantitatively describes the distributions. Our results are consistent with recent experimental observations of tubule assembly from triangular DNA origami monomers. The modeling framework elucidates design principles for assembling self-limited structures from synthetic components, such as artificial microtubules that have a desired width and chirality.

Thermodynamic Size Control in Curvature-Frustrated Tubules: Self-Limitation with Open Boundaries.

We use computational modeling to investigate the assembly thermodynamics of a particle-based model for geometrically frustrated assembly, in which the local packing geometry of subunits is incompatible with uniform, strain-free large-scale assembly. The model considers discrete triangular subunits that drive assembly toward a closed, hexagonal-ordered tubule, but have geometries that locally favor negative Gaussian curvature. We use dynamical Monte Carlo simulations and enhanced sampling methods to compute the free energy landscape and corresponding self-assembly behavior as a function of experimentally accessible parameters that control assembly driving forces and the magnitude of frustration. The results determine the parameter range where finite-temperature self-limiting assembly occurs, in which the equilibrium assembly size distribution is sharply peaked around a well-defined finite size. The simulations also identify two mechanisms by which the system can escape frustration and assemble to unlimited size, and determine the particle-scale properties of subunits that suppress unbounded growth.

Tiling a tubule: how increasing complexity improves the yield of self-limited assembly.

The ability to design and synthesize ever more complicated colloidal particles opens the possibility of self-assembling a zoo of complex structures, including those with one or more self-limited length scales. An undesirable feature of systems with self-limited length scales is that thermal fluctuations can lead to the assembly of nearby, off-target states. We investigate strategies for limiting off-target assembly by using multiple types of subunits. Using simulations and energetics calculations, we explore this concept by considering the assembly of tubules built from triangular subunits that bind edge to edge. While in principle, a single type of triangle can assemble into tubules with a monodisperse width distribution, in practice, the finite bending rigidity of the binding sites leads to the formation of off-target structures. To increase the assembly specificity, we introduce tiling rules for assembling tubules from multiple species of triangles. We show that the selectivity of the target structure can be dramatically improved by using multiple species of subunits, and provide a prescription for choosing the minimum number of subunit species required for near-perfect yield. Our approach of increasing the system's complexity to reduce the accessibility of neighboring structures should be generalizable to other systems beyond the self-assembly of tubules.

Yielding in an Integer Automaton Model for Amorphous Solids under Cyclic Shear.

We present results on an automaton model of an amorphous solid under cyclic shear. After a transient, the steady state falls into one of three cases in order of increasing strain amplitude: (i) pure elastic behavior with no plastic activity, (ii) limit cycles where the state recurs after an integer period of strain cycles, and (iii) irreversible plasticity with longtime diffusion. The number of cycles N required for the system to reach a periodic orbit diverges as the amplitude approaches the yielding transition between regimes (ii) and (iii) from below, while the effective diffusivity D of the plastic strain field vanishes on approach from above. Both of these divergences can be described by a power law. We further show that the average period T of the limit cycles increases on approach to yielding.

Cell Surface Protein mRNAs Show Differential Transcription in Pyramidal and Fast-Spiking Cells as Revealed by Single-Cell Sequencing.

The prefrontal cortex (PFC) plays a key role in higher order cognitive functions and psychiatric disorders such as autism, schizophrenia, and depression. In the PFC, the two major classes of neurons are the glutamatergic pyramidal (Pyr) cells and the GABAergic interneurons such as fast-spiking (FS) cells. Despite extensive electrophysiological, morphological, and pharmacological studies of the PFC, the therapeutically utilized drug targets are restricted to dopaminergic, glutamatergic, and GABAergic receptors. To expand the pharmacological possibilities as well as to better understand the cellular and network effects of clinically used drugs, it is important to identify cell-type-selective, druggable cell surface proteins and to link developed drug candidates to Pyr or FS cell targets. To identify the mRNAs of such cell-specific/enriched proteins, we performed ultra-deep single-cell mRNA sequencing (19 685 transcripts in total) on electrophysiologically characterized intact PFC neurons harvested from acute brain slices of mice. Several selectively expressed transcripts were identified with some of the genes that have already been associated with cellular mechanisms of psychiatric diseases, which we can now assign to Pyr (e.g., Kcnn2, Gria3) or FS (e.g., Kcnk2, Kcnmb1) cells. The earlier classification of PFC neurons was also confirmed at mRNA level, and additional markers have been provided.

Avalanches, thresholds, and diffusion in mesoscale amorphous plasticity.

We present results on a mesoscale model for amorphous matter in athermal, quasistatic (a-AQS), steady-state shear flow. In particular, we perform a careful analysis of the scaling with the lateral system size L of (i) statistics of individual relaxation events in terms of stress relaxation S, and individual event mean-squared displacement M, and the subsequent load increments Δγ, required to initiate the next event; (ii) static properties of the system encoded by x=σ_{y}-σ, the distance of local stress values from threshold; and (iii) long-time correlations and the emergence of diffusive behavior. For the event statistics, we find that the distribution of S is similar to, but distinct from, the distribution of M. We find a strong correlation between S and M for any particular event, with S∼M^{q} with q≈0.65. The exponent q completely determines the scaling exponents for P(M) given those for P(S). For the distribution of local thresholds, we find P(x) is analytic at x=0, and has a value P(x)|_{x=0}=p_{0} which scales with lateral system length as p_{0}∝L^{-0.6}. The size dependence of the average load increment 〈Δγ〉 appears to be asymptotically controlled by the plateau behavior of P(x) rather than by a subsequent apparent power-law behavior. Extreme value statistics arguments lead thus to a scaling relation between the exponents governing P(x) and those governing P(S). Finally, we study the long-time correlations via single-particle tracer statistics. The value of the diffusion coefficient is completely determined by 〈Δγ〉 and the scaling properties of P(M) (in particular from 〈M〉) rather than directly from P(S) as one might have naively guessed. Our results (i) further define the a-AQS universality class, (ii) clarify the relation between avalanches of stress relaxation and diffusive behavior, and (iii) clarify the relation between local threshold distributions and event statistics.

Diffusion in Mesoscopic Lattice Models of Amorphous Plasticity.

We present results on tagged particle diffusion in a mesoscale lattice model for sheared amorphous material in athermal quasistatic conditions. We find a short time diffusive regime and a long time diffusive regime whose diffusion coefficients depend on system size in dramatically different ways. At short time, we find that the diffusion coefficient, D, scales roughly linearly with system length, D∼L^{1.05}. This short time behavior is consistent with particle-based simulations. The long-time diffusion coefficient scales like D∼L^{1.6}, close to previous studies which found D∼L^{1.5}. Furthermore, we show that the near-field details of the interaction kernel do not affect the short time behavior but qualitatively and dramatically affect the long time behavior, potentially causing a saturation of the mean-squared displacement at long times. Our finding of a D∼L^{1.05} short time scaling resolves a long standing puzzle about the disagreement between the diffusion coefficient measured in particle-based models and mesoscale lattice models of amorphous plasticity.

Anisotropic Superattenuation of Capillary Waves on Driven Glass Interfaces.

Metrological atomic force microscopy measurements are performed on the silica glass interfaces of photonic band-gap fibers and hollow capillaries. The freezing of attenuated out-of-equilibrium capillary waves during the drawing process is shown to result in a reduced surface roughness. The roughness attenuation with respect to the expected thermodynamical limit is determined to vary with the drawing stress following a power law. A striking anisotropic character of the height correlation is observed: glass surfaces thus retain a structural record of the direction of the flow to which the liquid was submitted.

From depinning transition to plastic yielding of amorphous media: A soft-modes perspective.

A mesoscopic model of amorphous plasticity is discussed in the context of depinning models. After embedding in a d+1-dimensional space, where the accumulated plastic strain lives along the additional dimension, the gradual plastic deformation of amorphous media can be regarded as the motion of an elastic manifold in a disordered landscape. While the associated depinning transition leads to scaling properties, the quadrupolar Eshelby interactions at play in amorphous plasticity induce specific additional features like shear-banding and weak ergodicity breakdown. The latters are shown to be controlled by the existence of soft modes of the elastic interaction, the consequence of which is discussed in the context of depinning.

Finite-size effects in a model for plasticity of amorphous composites.

We discuss the plastic behavior of an amorphous matrix reinforced by hard particles. A mesoscopic depinning-like model accounting for Eshelby elastic interactions is implemented. Only the effect of a plastic disorder is considered. Numerical results show a complex size dependence of the effective flow stress of the amorphous composite. In particular, the departure from the mixing law shows opposite trends associated to the competing effects of the matrix and the reinforcing particles, respectively. The reinforcing mechanisms and their effects on localization are discussed. Plastic strain is shown to gradually concentrate on the weakest band of the system. This correlation of the plastic behavior with the material structure is used to design a simple analytical model. The latter nicely captures reinforcement size effects in (logN/N)(1/2), where N is the linear size of the system, observed numerically. Predictions of the effective flow stress accounting for further logarithmic corrections show a very good agreement with numerical results.