Developing new techniques
for single-molecule detection and bio-sensing
1. Short-range spectroscopic ruler (past achievement and current project)
2. Nano-electronic transistor for virus sensing and single-molecule detection (past achievement and current project)
1. Short-range spectroscopic ruler (past achievement and current project)
The detection of single biomolecules has transformed the way we study biological systems. It is now evident that proteins, RNA and even DNA molecules are much more dynamic than previously thought, exhibiting structural dynamics that are crucial to their function. Experiments that probe the behavior of individual molecules in real time have proven to be ideal for characterizing the structural dynamics of biomolecules and their functional implications. Förster resonance energy transfer (FRET) is the most widely adopted single-molecule technique for characterizing the conformational dynamics of biomolecules. It has been used successfully to probe the conformations of single biomolecules at relatively large length scales, i.e. on the order of several nanometers. While many critical structural dynamics of biomolecule occurs at shorter dimensions, few methods exist for the study of structural dynamics at these short length scales.
We have developed a highly efficient, all-optical, molecular switch based on short-range interaction between two organic molecules. This optical switch can function as a short-range ruler to reveal distance changes over length scales not currently accessible by other spectroscopic methods, and thus presents a new tool for studying the structural dynamics of biomolecules at the single-molecule level. We are currently test the performance of this new technique in a number of RNA systems.
We are also developing ultrafast FRET spectroscopy to extend the detection range of FRET into length scales of = 1nm.
2. Nano-electronic transistor for virus sensing and single-molecule detection (past achievement and current project)
W e are developing nano-electronic biosensors with single-molecule sensitivity. These devices are based on nanoscale field-effect transistors (FETs) made of semiconductor nanowires (Fig. 1). Specific binding of naturally charged bio-molecules to receptors on the nanowire can lead to depletion or accumulation of carriers in the nanowire and result in a change of its conductance. We have recently demonstrated that such a device can be used as a biosensor to detect viruses at the single-virion level in real time with high selectivity (Fig. 1). Multiplexed detection of several viruses simultaneously can be accomplished by modifying individual nanowire devices with antibodies specific for different viruses. The possibility of large scale integration of these nanowire devices suggests potential for simultaneous detection of a large number of distinct viral threats at the single virus level.
Sensitivity analysis of the devices suggests that such nano-transistors can potentially detect single protein, RNA and DNA molecules. We aim to develop this into a reliable technique for electrical detection of single biomolecules. Comparing to other existing single-molecule detection techniques, such as single-molecule fluorescence of force spectroscopy, the advantage of this electrical detection is that it relies on the natural charge state of the biomolecule and does not require special manipulation of the molecules, which may adversely perturb the biomolecule. This new method may be used for ultra-sensitive biosensing or for kinetic characterizations of biomolecular interactions, and should significantly expand our ability to detect and characterize microscopic biological entities.
Figure 1. Nano-electronic biosensor based on a nanowire FET. a , Schematic of the sensor. b , Sensing a single virus. Optical images taken at the indicated times (right panels) shows that the conductance decreases are caused by the binding of a single virus (red) to the nanowire (indicated by the white arrow).
Reference:
Our collaborators on the nano-electronic sensor project:
Links to our other research areas: