期刊
CHINESE SCIENCE BULLETIN-CHINESE
卷 66, 期 6, 页码 657-673出版社
SCIENCE PRESS
DOI: 10.1360/TB-2020-1051
关键词
nanopore sensors; DNA sequencing; 2D material; graphene; computer simulations
The passage of molecules through nanoscale pores is common in biology, and inspired the development of nanopore-based biosensors for probing, analyzing, and manipulating single biomolecules like DNA, RNA, and protein. These sensors offer advantages such as low cost, high efficiency, and ultra-long reads, making them promising for DNA sequencing applications, especially when using 2D material nanopores.
The passage of molecules through nanoscale pores is ubiquitous in biology. Inspired by this process, nanopore-based biosensors were proposed and have been widely used to probe, analyze or manipulate single biomolecules, such as DNA, RNA and protein. In a typical nanopore experiment, a thin membrane containing a nanoscale pore is used to separate two chambers of conducting electrolyte solution. As a transmembrane voltage bias is applied, analytes (such as DNA and RNA) in solution are driven through the nanopore, leading to changes in recorded ionic current traces. These changes are related to physical or chemical properties of the translocating molecules (analytes) such as structure, configuration and even identity. When DNA molecules are used as the analytes, the ionic current signal could be used to recognize individual bases, and in turn, the DNA sequence. The advantage of nanopore method for sequencing applications lies in its low cost, high efficiency, and ultra-long reads, because it eliminates the need for sample amplification and fluorescence labeling steps. In 1996, Kasianowicz et al. reported the first experiment of single-stranded DNA and RNA molecules passing through the biological pore alpha-hemolysin. In the following years, many other biological nanopores were used in order to obtain sufficient current and temporal resolution for single-molecule analysis. For example, the MspA nanopore, incorporated with Phi29 DNA polymerase, is able to read the sequence information of a single-stranded DNA (ssDNA) through measured ionic current. The relatively sharp and short constriction of the MspA nanopore compared to other biological nanopores (e.g., alpha-hemolysin) is regarded as the structural origin for its outstanding sensing ability. In particular, the length of the constriction in the MspA nanopore is equivalent to the distance between neighboring DNA bases in an ssDNA strand. This observation implied that a monolayer of typical two-dimensional (2D) materials such as graphene, with a thickness also equivalent to the spatial interval of DNA bases, is a promising candidate for DNA sequencing. On one hand, 2D material nanopores share inherent advantages of traditional solid-state nanopores, such as high stability over a broad range of temperature, pH and applied electric fields. On the other hand, the extreme thinness of 2D material nanopores is expected to deliver much higher spatial resolution than nanopores in traditional solid-state membranes such as silicon nitride and silicon oxide, which typically contain hundreds of bases in the pores simultaneously. Furthermore, the use of electrically conducting 2D materials offers the possibility to detect analytes at higher bandwidths, namely, by measuring transverse in-plane current through 2D material nanoribbons. During the development of nanopores sensors, computational tools such as first principle calculations and molecular dynamics simulations that can resolve molecular-scale interactions in nanopores have made significant contributions to this area in terms of prediction of novel detection approaches, optimization of device performance and explanation of experimental phenomena, etc. Here, with a standing point of computations and simulations, this review surveys the milestones in the area of 2D material nanopore-based biosensors, and the key experimental progress is also briefly discussed. Not limited to ionic current measurement, several other measurement methods such as transverse current in a nanoribbon and force traces during the pulling of biomolecules through nanopores are also introduced. This review further outlines key factors that restrict the performance of these sensors and discusses challenges and possible solutions. The key challenges include fast biomolecular translocation across nanopores and high noise levels in the recorded signal, etc. Finally, we provide a discussion on the future direction for the field, including the rational choice of 2D material, precise control over molecular movement inside nanopores as well as exploration of new applications.
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