Mesoscale matters

With flexibility parameters in hand, the researchers then attempted to skip directly to a whole-cell scale. Soon, however, they realized they were missing a critical view of membrane behavior: the mesoscale. Midway between the atomic and cellular scales, the mesoscale is a domain where the kinetic energy of all those jostling and bumping molecules causes measurable perturbations in the membrane. "This mesoscale methodology turned out to be absolutely essential. It was not just icing on the cake," Voth says.

Though run under the same conditions as the atomic-level simulation, the mesoscale membrane behaved very differently. Instead of the relatively uniform expansion observed in the atomic-scale model, the mesoscale view revealed ripples propagating across the membrane like waves traveling across the surface of the ocean. The higher the temperature, the larger the waves grew. Voth and Ayton found that such long wavelength undulations have a major effect on overall membrane behavior.

Other researchers had predicted the presence of these waves based on previous experiments. Some had even suggested that the phenomenon of ion channels flickering on and off unpredictably is a result of mesoscale bilayer undulations. "Undulations of the membrane may close over the top of an ion channel, causing it to quit working temporarily," Voth says. Membrane undulations could also help explain how ion channels sensitive to mechanical stress operate; when the membrane is stretched or stressed, the channel pore opens and allows molecules to stream in and out. "It's the perfect example of how mechanical motion is coupled to electrical or concentration gradients or flows of ions."

Using the mesoscale data, the researchers were able to construct an accurate model of the entire lipid bilayer. In this whole-cell, or continuum-level, model, individual molecules are no longer discernible. Instead, the model shows how undulations interact to either cancel one another or deform entire segments of the membrane. "This bridging has been one of the first successes, showing how a limited amount of molecular dynamics data can give you enough information to bridge out to a wider range of motions," Voth says.

Confident that their bridging techniques were robust, the researchers turned their attention to more realistic membrane compositions. The membranes of living cells contain much more than just lipids. Complex ion channels, cholesterol molecules, chemical receptors, and more stud its oily domain. When Voth and Ayton added cholesterol molecules to their virtual membranes, they found that the large sterol molecules increased the stiffness of the membrane at all scales and that the pure lipid membrane expanded the most during the simulation runs. For this reason, the concentration of sterols like cholesterol affect the overall elasticity of the membrane far beyond the atomic scale. The researchers reported their bridging results in Biophysical Journal in 2002.

The multiscale simulation techniques of Voth and Ayton should be applicable to plenty of other areas in biology. "Many phenomena people want to look at bridge length and time scales over many orders of magnitude, from angstroms to millimeters or femtoseconds to seconds," Voth says. "The grand vision is that by beginning with atomistic information, you will be able to work your way upward to simulating on a computer critical aspects of a living cell."

This research is supported by the National Institutes of Health.