Research

The general theme of my current research is to understand at the molecular level how cells transport small molecules into and out of the living cell. Transport occurs at the nanometre scale, with the conduction pathways having typical lengths of 2-10 nm and diameters ranging from the one of a water molecule (ca 0.28 nm) to 1 nm. Pores of these dimensions can be found in many systems (see right hand illustration, from top to bottom): Water transporting protein Aqp1 (pdb: 1H6I), a zeolite (class AFI) and a single-wall carbon nanotube; at the bottom a model pore is displayed that tries to capture the essential characteristics of the real pores.

Research interests top site menu

Molecular mechanism of sodium-coupled secondary transport

What are the conformational changes that comprise the transport cycle in the alternating access model of secondary transport? How is substrate transport (against a concentration gradient) coupled to the driving force, the transport of sodium down its electrochemical gradient? What is the source of ion and substrate specificity? Which mechanisms are common between transporters, which are different?

Sampling of conformational transitions

Typical equilibrium molecular dynamics simulations of membrane proteins range from between ~10 ns to 1 µs (10^-8s to 10^-6s) simulated time (numbers from 2010). Macromolecular transitions that underlie ion channel gating or substrate transport are thought to occur on the timescale of milliseconds to seconds (~10^-3s to 1s). Thus, standard simulations are more than 1000 times too short to capture these processes. I am using and developing advanced simulation methods such as umbrella sampling free energy calculations or dynamic importance sampling (DIMS) to obtain information on the energetics and the actual conformational changes underlying macromolecular transitions.

Water in molecular pores and ion channel gating

How does water behave once it is confined to very narrow slits or pores? Classical atomistic molecular dynamics simulations of water in model pores show a perhaps surprising dynamical complexity. I investigated the behaviour of water in hydrophobic nanopores by classical molecular dynamics (MD) simulations, which suggests how fast-switching ion channels in the nervous system can rapidly gate their currents.

Coarse grained approaches to ion permeation

Using higher level simulation methods like Brownian Dynamics one might be able to deduce functional properties of channels or pores even in the absence of atomistic structure data as long as lower resolution model is available. One example for some sort of coarse graining are lattice methods (see here a simple example for 2D spinodal decomposition with a Lattice-Boltzmann method).

Relating computational results to experimental measurements

Time scales of atomistic calculations are few orders of magnitude shorter than those of most experiments on ion permeation. Building up a hierarchy of approaches enables us to use simulations to relate to and explain experimental single channel measurements.