The villin headpiece subdomain
Like some previous projects, these simulations are studying the villin headpiece subdomain, pictured above, in a Generalized Born (GB) implicit solvent model. This protein is a very fast-folding system. Using the PS3 we're hoping to complete the most extensive sampling of this system in this particular GB model that has ever been attempted, possibly showing the simulation community its faults and strengths, once and for all.
What you might see on the screen:
In the PS3 simulation, the protein's backbone is shown as a ribbon threading the whole protein chain. In the folded state, you should see three chunks of the backbone which are each folded into helical shapes; these are the main elements of secondary structure in the villin headpiece.
Almost all of the bonds between atoms in the molecule are represented by thin lines. The bonds to hydrogen atoms are not shown in this representation, to simplify the display.
The first and last residues in the polypeptide chain are shown in "ball and stick" representation. The first, or N-terminal, residue is leucine, and the last, or C-terminal, residue is phenylalanine. Occasionally you will see the C-terminal phenylalanine associated with the phenylalanine residues constituting the hydrophobic core (see below ...). This is a non-native contact and may represent a misfolded structure.
Three phenylalanine residues constitute the hydrophobic core of the villin headpiece. These residues are represented as tubes or "licorice." These residues are vital to the folding of the villin headpiece: they are hydrophobic (that is, water-avoiding), and try to bury themselves into the core of the folded protein in order to avoid interacting with the solvent.
Two residues are shown in "spacefill" which are important in experiments on this system: the tryptophan at position 23 and the histidine at position 27. Tryptophan is able to absorb blue light and then re-emit that energy as light that is a little redder. If the histidine is close by, however, the tryptophan does not emit light after absorption. Instead, the energy is transferred to the histidine residue as heat. The histidine is said to quench the fluorescence of the tryptophan residue. This sytem forms an experimental probe of whether folding has occurred: if the protein is folded, these residues are likely to be in contact, meaning that the molecule is not very fluorescent. If the protein is unfolded, the histidine is not in contact with the tryptophan so that the fluorescence is more likely than the energy transfer. Examining the positions of these two residues in the computer simulation is an important benchmark for comparison with laboratory experiments.
List of Contributors
This project is managed by Daniel L. Ensign at .
Together, we are using large-scale simulation methods to unravel the mysteries of protein folding and related diseases, such as Alzheimer's Disease. We are continuing to use Folding@home in order to learn more about Alzheimer's Disease, in particular to discover new therapeutics, such as this recent work from our group.
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