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An important group of proteins, called mechanosensitive channels, are found in all living organisms, where they reside in the membranes that form cell walls. Like other membrane-channel proteins, MS channels open and close to provide a pathway for molecules to exit or enter the cell. The flow of ions-calcium, sodium and others-through membrane channels creates electrical signals that regulate neural and muscular activity. The special trait of MS channels, however, is their ability to open in response to mechanical stress-such as the pressure of a fingertip on a tabletop or vibrations in the air-and thereby trigger neural processes such as touch and hearing. An estimated 30 percent of the proteins in cells are membrane proteins, yet progress in understanding them has been slow because it's difficult to determine their structure. In 1998, however, structural biologists determined the structure of a bacterial MS channel, the bacterial large conductance mechanosensitive channel (MscL).

Although bacteria lack higher-animal perceptions like touch and hearing, MscL appears, nevertheless, to play an important role in their cells, acting as a safety valve during "osmotic shock." When a change in osmotic conditions induces water to flood into a cell, it can swell like a balloon to potentially burst and die. MscL protects against this by opening like a gate in response to pressure, allowing cytoplasmic material to escape.

With an elegant laboratory technique called "patch-clamp" experiments, researchers have been able to gather data about this MscL gating mechanism. These studies measure electrical current through the channel in relation to strain on the membrane, and they show no current, an absolutely nonleaky channel, until significant strain is applied. They also show that when the gate fully opens, it provides a "conductance pore" 30 angstroms across. The patch-clamp studies also indicate a staged process of opening, with several "subconductance states" of reduced current flow that precede the fully opened gate. These important experiments, however, offer no insight into the molecular details, no picture of what structural changes MscL undergoes as strain on the membrane opens the channel.

Professor Klaus Schulten's Theoretical Biophysics Group at Illinois has constructed a computational model of a section of cellular membrane containing the MscL channel. They created a patch of membrane consisting of 195 lipids, long-chain fatty molecules that form cell walls. To realistically simulate the cellular environment, they "hydrated" the membrane—placing it within a bilayer of 7,387 water molecules—yielding a molecular system of 55,666 atoms. Using a CRAY T3E at the Pittsburgh Supercomputing Center, they simulated this membrane-bilayer system with realistic conditions of temperature and pressure to allow it to "equilibrate," to fluctuate and find its natural state. In order to give a picture of what happens when the membrane is strained, MscL was placed in an even larger membrane (81,044 atoms) and surface tension was applied to the entire system. Results showed that the protein openes like an iris and tiltes to lie flatter in the membrane. Insights from simulation can be combined with experiment to construct a picture of how proteins and membranes function as an integrated mechanical system.

More information about this exciting work is available from Professor Klaus Schulten (Department of Physics and the Beckman Institute) or Physics graduate student Justin Gullingsrud.