p53
Over half of all cancers carry mutations in p53 — the protein called the guardian of the genome. p53's job is to detect damaged DNA and either trigger repair or, if the damage is too severe, order the cell to destroy itself. When p53 is broken, that quality-control system fails, and damaged cells survive and multiply.
To do its job, p53 has to find the right stretches of DNA and bind to them — and it can only do that when four copies of itself assemble into a tetramer. Many cancer mutations destabilize this assembly, so the tetramer never forms. Other mutations leave p53 intact but expose it to MDM2, a partner protein that tags p53 for destruction. Tumors often have plenty of p53 sitting around but no working tetramer to use it.
Folding@home has been simulating p53 since 2004 — the Pande lab's first cancer paper was on how the oligomerization domain folds (Chong et al., JMB 2004). Newer work simulates the p53–MDM2 interaction at the atomic scale, mapping the binding kinetics to guide treatments that could free p53 from MDM2's grip in tumors that still carry working copies.
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Dimerization of the p53 oligomerization domain: identification of a folding nucleus by molecular dynamics simulations
Journal of Molecular Biology. The Pande lab's first cancer paper. Chong, Snow, Rhee, Pande used F@H simulations to identify the folding nucleus of the p53 oligomerization domain.
Bridging microscopic and macroscopic mechanisms of p53–MDM2 binding with kinetic network models
F@H trajectories combined into a Markov state model of how p53 and MDM2 associate and dissociate — the binding event drugs would have to disrupt.
Interesting results from p53 projects
Update from the Pande lab on the early simulation findings that led to the 2005 paper.
Browse all F@H papers
Folding@home publications across cancer, infection, and neurological disease.