Visualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins

Wenzhe Liu, Limin Chen, Dongbao Yin, Zhiheng Yang, Jianfei Feng, Qi Sun (), Luhua Lai () and Xuefeng Guo ()
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Wenzhe Liu: Peking University
Limin Chen: Peking University
Dongbao Yin: Peking University
Zhiheng Yang: Peking University
Jianfei Feng: Peking University
Qi Sun: Peking University
Luhua Lai: Peking University
Xuefeng Guo: Peking University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Intrinsically disordered proteins (IDPs) play crucial roles in cellular processes and hold promise as drug targets. However, the dynamic nature of IDPs remains poorly understood. Here, we construct a single-molecule electrical nanocircuit based on silicon nanowire field-effect transistors (SiNW-FETs) and functionalize it with an individual disordered c-Myc bHLH-LZ domain to enable label-free, in situ, and long-term measurements at the single-molecule level. We use the device to study c-Myc interaction with Max and/or small molecule inhibitors. We observe the self-folding/unfolding process of c-Myc and reveal its interaction mechanism with Max and inhibitors through ultrasensitive real-time monitoring. We capture a relatively stable encounter intermediate ensemble of c-Myc during its transition from the unbound state to the fully folded state. The c-Myc/Max and c-Myc/inhibitor dissociation constants derived are consistent with other ensemble experiments. These proof-of-concept results provide an understanding of the IDP-binding/folding mechanism and represent a promising nanotechnology for IDP conformation/interaction studies and drug discovery.

Date: 2023
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DOI: 10.1038/s41467-023-41018-x

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