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.

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[Examples of nano pores: human Aqp1, zeolite (class AFI), (6,6)
carbon nanotube; model pore]
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.

The subject of my DPhil thesis was Gating mechanisms of ion channels. I investigated a 'hydrophobic gating mechanism' which appears to be realised in the nicotinic acetylcholine receptor ( nAChR) and possibly other ion channels such as MscS.

Transport in biological systems [top][site menu]

[cartoon of a cell with a membrane containing protein pores] A cell is a very complex system. It is encapsulated by a lipid membrane that is impermeable to most substances that the cell needs for functioning, especially polar species like water or ions or non-polar molecules like small sugars. In order to facilitate transport of these molecules the cell membrane contains a vast array of specialised proteins that either form "holes" or act as translocating machines. Because the process of staying alive depends on a finely regulated network of interactions which can depend sensitively on the concentrations of various solutes, transport must be tightly controlled.

Nature implements control by a twofold approach. Firstly, most transport proteins are highly selective, i.e. they are only permeable for a very limited range of permeators (for example, the potassium channel KcsA is 1000 times more permeable to K+ ions than to the very similar Na+ ions). Secondly, the protein can sense an external signal (e.g. a change in voltage across the membrane, a change in pH, a signal molecule) and correspondingly interrupt or allow the flow of the permeators, i.e. the "hole" can be open or closed. This is called gating.

Pores that are selective and have a gating mechanism are called channels; often, un-gated but selective protein-pores are referred to as porins. A third class of transport-proteins do not resemble holes but are complicated pumps which can translocate their substrates against a concentration gradient by harnessing the chemical power stored in ATP or an electrochemical gradient across the membrane.

Last modified: 2010-09-01 by Oliver Beckstein

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