研制具有亚纳米超高分辨率的原子力显微成像(AFM)系统，实现对蛋白大分子组合、细胞膜以及组织等复杂生物结构的直接解析，是结构生物学的重要目标之一。本项目针对生物医学中的这一重大科学需求，自主研发一种超高分辨的AFM系统。其核心内容包括：设计、构建在液氮温度下(Cryo)运行的调频（FM）与检测电子系统，低温非接触成像模块(Non-contact)，样品制备/传输模块，常压低温控制系统等，从而实现亚纳米尺度的超分辨结构解析能力。该系统的研制成功，对于随机分布的复杂生物大分子或组合、细胞乃至组织切片，将建立具有最高点分辨能力的成像技术与方法，为单分子结构生物学、分子生物物理学、结构细胞生物学、高分辨病理与微观解剖学、药物开发、纳米医学等领域提供一种具有独立知识产权的全新技术途径，并填补目前电子显微技术与光学成像技术在分辨尺度上的空缺，必将成为具有广泛生物医学应用的独特而重要的手段之一。

The ultimate objective of this project is to develop a novel functional atomic force microscope (AFM) that can achieve nm to sub-nm spatial resolution on individual macromolecules and heterogeneous complexes, including nanoscale biological machines. Although it has been a long-term goal to directly detect sub-molecular features and structural changes within supra-molecular complexes, which is essential for the elucidation of their functions, this level of resolution has not been reproducibly achieved by AFM with single (bio-)macromolecules at present. Since protecting the sharpness of an AFM tip is most critical to achieve nm to sub-nm resolution with biological structures preserved by low temperature, the only solution is to introduce the mode of frequency modulation (FM) non-contact imaging to prevent the sharp tip apex of only a few atoms from disintegrating during imaging. We propose to directly examine the most basic determinants of non-contact cryo force imaging with an unconventional approach of nitrogen vapor purged environment to ensure a contamination free system while retaining a sufficient sensitivity for the non-contact operation. The successful completion of the project will lead to the implementation of a new Cryo FM Non-Contact AFM imaging system with sub-nm resolution as well as the techniques and methodologies for imaging single molecules with this super-resolution AFM, which will build the foundation for its prospective applications in structural biology, molecular biophysics, drug development and nano-medicine.