Modeling of Kinetic Processes

Transport of Chemicals Through Proteins

The entrance and exit paths of chemicals, called tunnels, to enzymes are hypothesized to be an important selectivity filter for their enzymatic reaction. To identify and investigate tunnels in proteins, we have recently developed a stepwise scheme, titled IterTunnel, which allows tunnels to be iteratively re-calculated during a steered MD simulation. In comparison with existing methods, the major advantage of our method is that it allows the protein to adapt its conformation to the ligand as the ligand traverses through the protein. Unlike existing methods, our approach is designed to identify tunnels that may open as a result of protein flexibility. In the future, we will systematically investigate how structurally different chemicals use different tunnels, how substrate and product might enter and exit through different pathways and how this influences kinetic association and dissociation rates.


Kingsley L.J., Lill M.A. Substrate tunnels in enzymes: structure-function relationships and computational methodology. Proteins 83, 2015, 599-611.

Kingsley, L.J.; Lill, M.A. Including ligand-induced protein flexibility into protein tunnel prediction. J. Comput. Chem. 35, 2014, 1748-1756.

Kingsley, L.J., Lill, M.A. Ensemble generation and the influence of protein flexibility on geometric tunnel prediction in cytochrome P450 enzymes. PLoS One 9, 2014, e99408.

Kinetics in cells

We developed coarse-grained Monte Carlo simulation approaches to simulate the kinetics of soluble and membrane-anchored proteins in cellular context. Those methods have been applied in several different collaboration with experimental single-molecule biophysics research groups (collaborations with Prof. Ken Ritchie, Purdue; Prof. Bert Hecht, Basel; Prof. Uli Aebi, Basel; Prof. Horst Vogel, Lausanne). In these collaborations, we studied (1) the lateral diffusion of the ferric enterobactin transporter FepA and TonB in the membranes of E. coli, (2) the interaction of hepatitis B virus capsids lacking a nuclear localization signal with nuclear pore complexes (NPCs), and (3) the influence of GPCR signaling activity on its mobility in membranes.

Lill, Y.; Jordan, L.D.; Smallwood, C.R.; Newton, S.M.; Lill, M.A.; Klebba, P.E.; Ritchie, K. Confined mobility of TonB and FepA in Escherichia coli membranes. PLoS One 9, 2016, e0160862.

Lill, Y.; Kaserer, W.A.; Newton, S.M.; Lill, M.A.; Klebba, P.E.; Ritchie, K.P. A single molecule study of molecular mobility in the cytoplasm of E. coli. Phys. Rev. E. 86, 2012, 021907.

Lill, Y.; Lill, M.A.; Fahrenkrog, B.; Schwarz-Herion, K.; Paulillo, S.; Aebi, U.; Hecht, B. Single Hepatitis-B virus core capsid binding to individual nuclear pore complexes in HeLa cells. Biophys.J. 91, 2006, 3123-3130.

Lill, Y.; Martinez, K. L.; Lill, M.A.; Meyer, B.H.; Vogel, H.; Hecht, B. Kinetics of the initial steps of G-protein coupled receptor mediated cellular signaling revealed by single molecule imaging. ChemPhysChem 6, 2005, 1633-1640.