Poster Presentation 2014 International Biophysics Congress

Single-molecule enzymology with ClyA nanopores (#366)

Annemie Biesemans 1 , Misha Soskine 1 , Giovanni Maglia 1
  1. KU Leuven, Heverlee, Belgium

Single-molecule methods provide powerful tools to investigate conformational changes, transient subpopulations and the dynamics of enzymes that are usually hindered by ensemble averaging. In this work we use Cytolysin A (ClyA) nanopores to observe the conformational changes of native enzymes in real-time. Under an applied potential single AlkB DNA demethylase enzymes are reversibly confined inside ClyA by an electroosmotic flow, while the ionic current through the nanopore provides a high-bandwidth signal that is used to probe the dynamics and ligand-induced folding of the native proteins. The binding of ligands to AlkB induces ~5% enhancements to the current signal, reflecting the transition from the open conformation of the apo-enzyme to the closed ligand-bound state. Furthermore, changes in the dynamics of the trapped enzymes upon binding to the ligands are observed by changes in the frequency of the AlkB current signal. Voltage dependencies of the ligand-induced transitions indicate that AlkB maintains a native-like function when integrated inside ClyA. Kinetic analysis of the binding events allows accurate determination of both fast and slow kinetic rate constants, and our results reveal that ligand binding to AlkB is compatible with an induced-fit molecular recognition mechanism. Therefore, current recordings of individual enzymes confined inside a nanopore provide new means to explore enzyme dynamics and conformational changes. Measurements during tens of minutes with millisecond time resolution surpass the temporal limitations of fluorescence spectroscopy, without the complexity related to enzyme labeling or immobilization.