William B. Sherman

Amnesia: A Function of the Temporal Relation of Footshock to Electroconvulsive Shock

When rats received a brief footshock upon stepping off an elevated platform, and an electroconvulsive shock 30 seconds or 6 hours afterward, amnesia was not observed 24 hours later. If a second footshock (noncontingent) was delivered 0.5 second before the electroconvulsive shock, amnesia was observed. The amnesia was temporary if conditioning was strong and permanent if conditioning was weak.

Amyloid fibrils nucleated and organized by DNA origami constructions

Amyloid fibrils are ordered, insoluble protein aggregates that are associated with neurodegenerative conditions such as Alzheimer’s disease1. The fibrils have a common rod-like core structure, formed from an elongated stack of β-strands, and have a rigidity similar to silk (Young’s modulus of 0.2-14 Gpa)2. They also exhibit high thermal and chemical stability3, and can be assembled in vitro from short synthetic non-disease-related peptides4,5. As a result, they are of significant interest in the development of self-assembled materials for bionanotechnology applications6. Synthetic DNA molecules have previously been used to form intricate structures and organize other materials such as metal nanoparticles7,8, and could in principle be used to nucleate and organize amyloid fibrils. Here we show that DNA origami nanotubes can sheathe amyloid fibrils formed within them. The fibrils are built by modifying the synthetic peptide fragment corresponding to residues 105-115 of the amyloidogenic protein transthyretin (TTR)9, and a DNA origami10 construct is used to form 20-helix DNA nanotubes with sufficient space for the fibrils inside. Once formed, the fibril-filled nanotubes can be organized onto predefined two-dimensional platforms via DNA-DNA hybridization interactions.

Assembly pathway analysis of DNA nanostructures and the construction of parallel motifs.

We present a system for analyzing the assembly pathway of DNA nanostructures. This enables the identification, explanation, and avoidance of obstacles to proper structure formation. Potential problems include strand end-pinning and misfolding caused by the structural bias of nominally flexible junctions. We have used this system to guide the construction of parallel motifs that had previously, for unknown reasons, resisted assembly.

Metallic Nanoparticles Used to Estimate the Structural Integrity of DNA Motifs

Branched DNA motifs can be designed to assume a variety of shapes and structures. These structures can be characterized by numerous solution techniques; the structures also can be inferred from atomic force microscopy of two-dimensional periodic arrays that the motifs form via cohesive interactions. Examples of these motifs are the DNA parallelogram, the bulged-junction DNA triangle, and the three-dimensional-double crossover (3D-DX) DNA triangle. The ability of these motifs to withstand stresses without changing geometrical structure is clearly of interest if the motif is to be used in nanomechanical devices or to organize other large chemical species. Metallic nanoparticles can be attached to DNA motifs, and the arrangement of these particles can be established by transmission electron microscopy. We have attached 5 nm or 10 nm gold nanoparticles to every vertex of DNA parallelograms, to two or three vertices of 3D-DX DNA triangle motifs, and to every vertex of bulged-junction DNA triangles. We demonstrate by transmission electron microscopy that the DNA parallelogram motif and the bulged-junction DNA triangle are deformed by the presence of the gold nanoparticles, whereas the structure of the 3D-DX DNA triangle motif appears to be minimally distorted. This method provides a way to estimate the robustness and potential utility of the many new DNA motifs that are becoming available.

3D Fractal DNA Assembly from Coding, Geometry and Protection

We present DNA components whose 3D geometry and cohesive portions are compatible with a fractal 3D assembly. DNA parallelograms have been proposed in Carbone and Seeman [(2002b) Natural Computing 1: 469–480; (2003) Natural Computing 2: 133–151] as suitable building blocks for a 2D fractal assembly of the Sierpinski carpet. Here we use Mao 3D triangles, which are 3D geometrically trigonal molecules, to construct basic building blocks and we obtain a simplified version of the 2D assembly design. As in the previous 2D construction, we utilize the interplay of coding in the form of cohesive ends, geometrical complementarity and protection of potentially undesirable sites of reactivity. The schema we propose works for trigonal symmetries and the Mao triangle is one example of a possible DNA trigonal tile.

Structural DNA nanotechnology: molecular construction and computation

Structural DNA nanotechnology entails the construction of objects, lattices and devices from branched DNA molecules. Branched DNA molecules open the way for the construction of a variety of N-connected motifs. These motifs can be joined by cohesive interactions to produce larger constructs in a bottom-up approach to nanoconstruction. The first objects produced by this approach were stick polyhedra and topological targets, such as knots and Borromean rings. These were followed by periodic arrays with programmable patterns. It is possible to exploit DNA structural transitions and sequence-specific binding to produce a variety of DNA nanomechanical devices, which include a bipedal walker and a machine that emulates the translational capabilities of the ribosome. Much of the promise of this methodology involves the use of DNA to scaffold other materials, such as biological macromolecules, nanoelectronic components, and polymers. These systems are designed to lead to improvements in crystallography, computation and the production of diverse and exotic materials. Branched DNA can be used to emulate Wang tiles, and it can be used to construct arbitrary irregular graphs and to address their colorability.

Building a Better Nano-Biped

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A zwitterion-DNA coating stabilizes nanoparticles against Mg2+ driven aggregation enabling attachment to DNA nanoassemblies

Plasmonics and photonics demand new methods for the controlled construction of nanoparticle (NP) arrays. Complex, low-symmetry configurations of DNA-functionalized NPs are obtained by connection to scaffolds of branched and folded DNA nanostructures. However, the stabilization of these branched structures by Mg(2+) counterions also drives the uncontrolled aggregation of NPs. We demonstrate, using a two-dimensional DNA scaffold, that derivatizing gold nanoparticles (AuNPs) with zwitterionic ligands overcomes this problem.

Atomic force microscopy of arrays of asymmetrical DNA motifs

DNA can easily be assembled into wide and relatively flat nanostructures that lend themselves to study viaAtomic Force Microscopy (AFM). It is often important to know which side of an assembly the AFM is imaging. This is particularly crucial for characterizing nanomachines, where the movement must be measured relative to fiducial features visible to the AFM. We have developed a cheap and simple technique for building DNA arrays with distinguishable sides, a technique requiring 10 or fewer strands – dozens or hundreds of strands fewer than used for these purposes previously. Our approach involves constructing arrays out of DNA tiles that have low apparent symmetry when imaged viaAFM. We have surveyed the effects of varying degrees of motif asymmetry in AFM micrographs. Even at resolutions where the individual tiles cannot be resolved (either because of sub-optimal tip quality, or very gentle tapping by the AFM tip) the larger scale features of the arrays have predictable structures that allow the determination of which side of the array is facing up. We have used this information to verify that DNA hairpins attached to either the up- or down-facing side of an array on mica can be detected in AFM height scans. We have also characterized differences in appearance between hairpins attached to different sides of the arrays.

HolT Hunter: software for identifying and characterizing low-strain DNA Holliday Triangles.

Synthetic DNA nanostructures are most commonly held together via Holliday junctions. These junctions allow for a wide variety of different angles between the double helices they connect. Nevertheless, only constructs with a very limited selection of angles have been built, to date, because of the computational complexity of identifying structures that fit together with low strain at odd angles. I have developed an algorithm that finds over 95% of the possible solutions by breaking the problem down into two portions. First, there is a problem of how smooth rods can form triangles by lying across one another. This problem is easily handled by numerical computation. Second, there is the question of how distorted DNA double helices would need to be to fit onto the rod structure. This strain is calculated directly. The algorithm has been implemented in a Mathematica 8 notebook called Holliday Triangle Hunter. A large database of solutions has been identified. Additional interface software is available to facilitate drawing and viewing models.