The program relies on Wolynes' groundbreaking principle of minimal frustration to determine how the energy associated with amino acids, bead-like elements in a monomer chain, determines their interactions with their neighbors as the chain folds into a useful protein.
Proteins usually fold and unfold many times as they carry out their tasks, and each cycle is an opportunity for it to misfold. When that happens, the body generally destroys and discards the useless protein. But when that process fails, misfolded proteins can form the gummy amyloid plaques often found in the brains of Alzheimer's patients.
The titin proteins the Rice team chose to study are not implicated in disease but have been well-characterized by experimentalists; this gives the researchers a solid basis for comparison.
"In the real muscle protein, each domain is identical in structure but different in sequence to avoid this misfolding phenomenon," Wolynes said. So experimentalists studying two-domain constructs made the domains identical in every way to look for the misfolding behavior that was confirmed by Rice's earlier calculations. That prompted Wolynes and his team to create additional protein models with three and four identical domains.
"The experiments yield coarse-grained information and don't directly reveal detail at the molecular level," Schafer said. "So we design simulations that allow us to propose candidate misfolded structures. This is an example of how molecular models can be useful for investigating the very early stages of aggregation that are hard to see in experiments, and might be the stages that are the most medically relevant."
"We want to get the message across that this is a possible scenario for misfolding or aggregation cases -- that this branching does exist," Zheng added. "We want experimentalists to know this is something they should be looking for."
Wolynes said the lab's ne
|Contact: David Ruth|