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Research Vision
Many biological processes cannot be fully understood from static structures alone. Proteins and biomolecular assemblies often function through transient conformational changes, weak interactions, dynamic self-assembly, and mechanical responses to their environment. These events are frequently heterogeneous, short-lived, and difficult to synchronize, making them challenging to capture using ensemble measurements.
The Lin Lab aims to bridge this gap by developing and applying approaches that allow us to watch biological molecules work in real time. Our long-term vision is to establish HS-AFM and integrated biophysical analysis as a quantitative platform for understanding how molecular structure, dynamics, mechanics, and function are coupled in living systems.
Real-Time Molecular Imaging of Structure, Dynamics, and Function
The Lin Research Group studies the structural and functional dynamics of biomolecules, including proteins, nucleic acids, and biological membranes, at the single-molecule and nanoscale levels. Biological function is inherently dynamic: proteins change conformation, diffuse, assemble, interact with molecular partners, and respond to their surrounding environments. Capturing these processes in action is essential for understanding how molecular structure gives rise to biological function.
To address this challenge, we develop and apply high-speed atomic force microscopy (HS-AFM) and integrate it with complementary biochemical, biophysical, and cellular approaches. These include protein expression and purification, cell culture, fluorescence microscopy, electron microscopy, electrophysiology, biochemical activity assays, and computational analysis.
Our goal is to visualize and quantify biomolecular dynamics in physiologically relevant environments with nanometer spatial resolution and millisecond temporal resolution. By combining real-time molecular imaging with functional measurements and computational analysis, we aim to uncover the mechanisms that drive complex biological processes, from protein conformational dynamics and molecular self-assembly to DNA repair, membrane remodeling, and cellular regulation.
Our Multidisciplinary Approach
High-speed atomic force microscopy and force spectroscopy
Real-time imaging and mechanical measurements of biomolecules, molecular assemblies, membranes, and soft biological materials in liquid.
Protein expression, purification, and biochemical reconstitution
Production and preparation of purified protein systems for mechanistic studies of structure, dynamics, assembly, and function.
Cell culture and cell-based systems
Cellular preparation and validation of biologically relevant protein systems, including membrane-associated and disease-related proteins.
Single-molecule biophysics and structural biology
Direct visualization and quantitative analysis of molecular intermediates, conformational states, and dynamic molecular interactions.
Complementary biophysical and functional assays
Integration of biochemical activity assays, binding assays, fluorescence microscopy, electron microscopy, electrophysiology, and other approaches to connect molecular dynamics with biological function.
Image processing, machine learning, and kinetic modeling
Computational analysis of complex AFM movies and single-molecule trajectories to extract structural, dynamic, and kinetic information.
Novel instrumentation and method development
Development of new AFM hardware, imaging modes, analytical tools, and quantitative methods to expand the capabilities of real-time molecular imaging.
1. DNA–Protein Interactions and Genome Maintenance
DNA Topological Dynamics
Watching proteins bind, move, cleave, repair, and organize DNA.
DNA-associated reactions are highly dynamic and often involve transient intermediates that are difficult to capture by static structural methods. We use HS-AFM, designed DNA substrates, purified proteins, biochemical assays, and computational analysis to study nuclease activity, DNA repair, microhomology-mediated end joining, CTCF-mediated DNA organization, nucleosomes, and DNA damage responses.
Keywords: DNA repair, DNase I, G2L4 RT, CTCF, nucleosomes, chromatin, genome maintenance
2. Protein Assembly and Functional Regulation
Realtime dynamics of Annexin-V lattice on membrane with newly developed image reconstruction technique.
Understanding how dynamic protein organization regulates biological function.
Many proteins function through higher-order assembly, ligand-dependent conformational changes, and reversible interactions. We combine HS-AFM, protein expression and purification, biochemical reconstitution, enzymatic assays, structural modeling, and molecular simulations to study how protein assemblies form, remodel, and regulate function, including ligand-dependent assembly of metabolic enzymes such as PFKL.
Keywords: protein assembly, PFKL, enzyme regulation, glycolysis, ligand response, molecular simulations
3. Membrane Proteins and Biological Interfaces
Membrane-reconsituted OmpF trimers viewed from extracellular side (Left) and periplasmic side (Right).
Revealing how proteins interact with membranes and biological surfaces.
Membrane proteins and membrane-associated assemblies are central to infection, signaling, transport, and cellular organization. We combine HS-AFM, membrane reconstitution, cell culture, protein biochemistry, and complementary biophysical techniques to study viral proteins, lipid bilayers, protein–membrane interactions, and conformational dynamics at biological interfaces.
Keywords: membrane proteins, SARS-CoV-2 spike, lipid bilayers, protein–membrane interactions, cell culture, conformational dynamics
4. High-Speed AFM Technology and Quantitative Imaging
HS-AFM Systems
Visualizing molecular dynamics with next-generation nanoscale imaging.
We develop and apply high-speed atomic force microscopy technologies to visualize biomolecules, molecular assemblies, and soft biological materials in real time. Our work advances HS-AFM through FPGA-based signal processing, contact mechanics, viscoelasticity analysis, and machine-learning-based image analysis.
Keywords: HS-AFM, instrumentation, FPGA, image analysis, single-molecule kinetics
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