Organisms dynamically recombine node connections through topological transformations to form a topological mode that adapts to the environment, thereby improving the efficiency of signal propagation in complex environments.
For example, although brain networks are limited to three-dimensional space, cortical folds connect distant neurons and provide shortcuts to quickly transmit signals.
Similarly, chromatin folding links enhancers to promoters, activating transcription factors that precisely regulate the expression of some 20,000 genes.
The principle that organisms cleverly use topological transformations to optimize local information dissemination has inspired the design of biomolecular computations. Recently, scientists have also made new progress in the development of relevant computational models.
Professor Pei Hao of East China Normal University and the team of Academician Fan Chunhai of Shanghai Jiao Tong University jointly developed a topologically programmed DNA origami system.
This deformable origami technology enabled by topological changes in DNA nanostructures enables the construction of dynamic frameworks at the nanoscale to encode the connectivity and network connectivity between signal nodes, and a breakthrough in graphically computing at the molecular scale.
"The degree of complexity control achieved by the DNA system we constructed at the single-molecule scale is at the forefront of the reported artificial molecular systems, which provides a new direction for the computational design of molecular graphics." Pei Hao said.
The process covers more than 100 chain displacement reactions and enables efficient topological transformations of hybridization reactions at the molecular level.
The study demonstrates the use of DNA origami technology as a programmable dynamic framework for topological graphical calculations at the nanoscale. In the experiment, they successfully demonstrated a signaling network with up to 77 molecular nodes.
Commenting on the study, the reviewers said, "The study takes the concept to the next level by implementing more advanced topological transformations through 'cutting' operations, and describes their systems in correct mathematical topological terms such as lattice, number of boundaries, and directionability." ”
Picture丨Pei Hao (Source: Pei Hao)
The topologically programmed DNA origami system is expected to provide new ideas for a wide range of fields, from biomedical to materials science.
Specifically, it has great application potential in the development of intelligent molecular computing systems, directed drug release, diagnostic testing, and intelligent nanomaterials.
In terms of the development of intelligent molecular computing systems, researchers have demonstrated that the DNA origami system can be used as a computational scaffold to achieve reconfigurable logical operations, and has demonstrated multiple advantages for computational system development, including molecular orthogonality, cross-reactivity, etc.
"If we can combine topological allosterism with external environmental stimuli, so that the DNA structure can respond to external stimuli for topological allosterism and then modulate the computational function, it is expected that we can build adaptive and more intelligent molecular computing systems." Pei Hao said.
It is important to understand that such responsive computing devices can be embedded in biological materials such as cells, tissues, serum, etc., and can perform calculations in response to specific signals in the body, such as pH or temperature changes, to achieve molecular diagnostics, so as to achieve precise drug delivery, intelligent diagnosis and treatment, improve the effectiveness of treatment, and reduce side effects.
图丨期刊当期封面（来源：Nature Chemistry）
日前，相关论文以《基于拓扑编程的 DNA 折纸结构中的分子信号传播编码》（Encoding signal propagation on topology-programmed DNA origami）为题，以期刊封面形式发表在 Nature Chemistry[1]。
Ji Wei, Xiong Xiewei, Cao Mengyao, and Zhu Yun, Ph.D. students from East China Normal University, are the co-first authors, and Professor Pei Hao of East China Normal University and Academician Fan Chunhai of Shanghai Jiao Tong University serve as co-corresponding authors.
图丨相关论文（来源：Nature Chemistry）
The essence of life lies in the storage, encoding and decoding of information. Based on the simulation of DNA molecules in nature, storing high-density information and accurately expressing genes, Academician Fan Chunhai's team began to try to build an artificial molecular system to process molecular information.
The seven-year-long study is a highly interdisciplinary effort that integrates the fields of topology, computing, molecular biology, and chemistry to involve ingenious molecular origami structure design and matching DNA single-molecule circuit architectures to explore molecular-based graphical computations.
Hao Pei's group is committed to the development of synthetic biomolecule computing systems with information processing capabilities. However, the design of such a complex and ingenious molecular structure was also a "first" for them.
There are many design factors that need to be considered for such a global conformational change, such as stresses and torsional forces at the molecular level, which need to be continuously adjusted through simulation.
They have used a variety of design software and experimental verification to complete the entire design process from geometric model, coarse-grained model, to sequence design generation and simulation.
图丨基于 DNA 折纸系统的拓扑转换与计算（来源：Nature Chemistry）
In this study, the topological changes of the macromolecular assembly system composed of DNA molecules were artificially and precisely controlled. The researchers studied the signaling of individual molecules on this structure and demonstrated two successive topological transformations of 3 different DNA origami structures.
In addition, the system can switch between three multi-purpose, programmable dual-track circuits for continuous calculation functions and has a variety of logic calculation functions.
Based on the topological alloterostructure to realize the transformation of the connection mode of computing network nodes, the system shows extremely high topological programmability at the nanoscale, which provides a new design idea for topological graphical computing.
In the experimental phase, the assembly of origami structures is essentially the process of molecular hybridization to the final steady state, and a suitable experimental condition setting is crucial, and the researchers tried a variety of experimental condition settings, including subsequent purification conditions, to optimize the assembly efficiency and yield of origami.
The results showed that the assembly efficiency of the initial origami could reach more than 80%, and the topological allosteric efficiency was more than 70%.
Notably, this study succeeded in propagating the signal on a three-dimensional origami-shaped surface along a path of more than about 300 nm in length in different directions and with different curvatures (concave/convex).
"This is similar to the domino effect we are familiar with, where the unraveling of one hairpin molecule leads to the unwinding of a series of molecular hairpins, thus enabling the transmission of molecular signals on a 3D surface," Pei explains. ”
This signal propagation mode makes spatial organization one of the main factors controlling molecular signal transmission, which can greatly reduce the requirement for the orthogonality of molecular components.
In addition, the signal transmission speed is very fast, and the distance spacing between the hairpin molecules greatly reduces the cross-reactivity between molecules.
In the future, it is expected that more complex molecular computing systems will be developed based on this, and new solutions will be provided to the design difficulties and cross-reactivity problems faced by the scale expansion of molecular circuits.
图丨可重构拓扑 DNA 折纸的设计和可视化（来源：Nature Chemistry）
It is understood that researchers will continue to pay attention to related problems and find solutions in the subsequent research stage.
First of all, the complexity of topology needs to be further improved, and future research will focus on how to build more complex and dynamic topologies and achieve higher levels of programmability.
This involves the development of new design and simulation tools adapted to the needs of topology programming, enabling topologies to be programmed and operated with greater precision.
Secondly, the stability of the structure will directly affect its application potential in the biological environment.
In the next step, the group plans to explore how to enhance the stability and durability of topologies, especially to maintain their function and shape under changes in the external environment (e.g., temperature, pH, ion concentration, etc.) or complex operating conditions, which may require improved materials or optimized structural design.
In addition, the existing graphical computing power of topology is still limited, so the team will explore how to improve computing power through more complex topology design, multi-structure combination, development of new computational models, and parallel computation combined with multi-origami structures.
At the same time, they will work more deeply with Academician Fan Chunhai to extend topological graphical computing to areas such as DNA storage, nano-diagnosis and treatment, and precision medicine.
If DNA origami-based DNA storage can be combined with topological graphical computing, it is expected that a new DNA storage system integrating storage and computing can be constructed.
"This is not only able to store information, but also to directly process the stored information in situ, and we look forward to our cooperation to jointly promote the rapid development of the field." Pei Hao said.
Resources:
1.Ji, W., Xiong, X., Cao, M.et al. Encoding signal propagation on topology-programmed DNA origami. Nature Chemistry 16, 1408–1417 (2024). https://doi.org/10.1038/s41557-024-01565-2
Typesetting: Chu Harvest