Form Follows Sequence

Models that derive values from real amino-acid residues and realistic watery environments can help us understand the folding of real proteins, and the shapes and functions of many unknown proteins can be deduced from libraries of known folds. These and yet more sophisticated and powerful computer techniques are essential, for a functioning protein is dynamic, while the protein structures determined by crystallography are static-and even at the present rapid experimental clip it could take another century to decipher the full atomic structures of all the proteins in cells by experiment alone.

Daniel Rokhsar and his colleagues have also studied the molecular dynamics of a real protein structure, not under natural conditions or in an experimental set-up, but in silico, using a fully realistic "all-atom" computer model in which the properties of every atom in every amino acid are represented, and thousands of water molecules are explicitly treated.

"Even in long runs on powerful computers, with all-atom calculations it's only practical to model a few nanoseconds of real time," says Rokhsar, "yet real proteins typically fold up in a few milliseconds"-a million times longer. "So we modeled a very small part of a real protein, a common structure called a beta hairpin. Instead of trying to watch it fold up, we watch it unfold, which at the high temperatures of the simulation is a much quicker process."

Unfolding occurs in a series of discrete steps which always happen in the same order. Each represents the dissolution of a specific part of the hairpin structure, recalling the transition states of lattice models.

Much faster and more manageable supercomputers will be needed to study larger protein structures at the atomic level. The largest yet studied in silico, with 36 residues and 12,000 atoms, was tracked over the course of a single microsecond by researchers at the University of California at San Francisco; the simulation took a Cray T3D and a Cray T3E-600 running for two months each, and the model did not reach the real protein's native conformation.

To rationally design drugs that can attack specific disease mechanisms, to create novel industrial enzymes, to engineer new organisms that can increase food production, clean up waste, and restore the environment-these potential benefits all depend upon accurate, intimate knowledge of a wide range of protein structures and their possible mutations. Every scrap of experimental knowledge, every advance in calculating the molecular dynamics of model proteins, all are essential to the solution of the protein folding problem, a goal that still glimmers in the future.