Angewandte Chemie International Edition
© WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
For full article and contact information, see Angew. Chem. Int. Ed. 2001, 40 (2), 351-355
Folding Proteins on a Computer
Proteins only function
when properly folded
In order for enzymatic reactions to proceed correctly, the enzyme and substrate must fit together as precisely as a lock and key. The function of the enzyme and protein is determined by the structure of the latter. The chain of amino acids that makes up the protein thus has to fold in a very precise fashion. Nothing had better go wrong: the cattle epidemic of BSE seems to have stemmed from an incorrectly folded protein.
How the folding process of proteins proceeds on an atomic level has so far not been experimentally determined. A team of chemists working with Wilfred van Gunsteren is now hot on the heels of protein folding with the help of computer simulations.
The number of possible conformations that a protein can theoretically adopt rises exponentially with the length of its chain of amino acids. This quickly reaches astronomical orders of magnitude, making it impossible to test all of the possibilities on a computer. Thanks to the enormous computing power of modern supercomputers, it is now at least possible to simulate the folding of very short peptide chains. Repulsion and attraction between individual atoms determine the balance between the folded (native) and unfolded (denatured) states of the protein. Taken together, all of the spatial characteristics of these forces make up a force field. Van Gunsteren recognized that it is necessary to precisely represent both the final folded state and the unfolded starting state of the protein as force fields in order to simulate the folding process. A hopeless task, it seemed - the number of theoretically possible unfolded states is simply too huge.
Precisely this assumption has now been revealed to be false. In fact, the number of states is actually comparatively small, as revealed by simulations carried out for several small peptides. "This discovery pushes the simulation of protein folding processes within reach," says van Gunsteren optimistically.
But how does one come up with the necessary force field for the unfolded protein when there is no experimental data available? Van Gunsteren and his colleagues made do with data on the interactions within and between small molecules in solution. Starting with this carefully worked out force field, the team was in a position to simulate the folding of a series of peptides.
If this method of simulating the folding process also works for larger proteins, one of the fundamental challenges of molecular biology comes within reach: the prediction of the spatial structures of unknown proteins.