A method by Rice University researchers to model the way proteins fold -- and sometimes misfold -- has revealed branching behavior that may have implications for Alzheimer's and other aggregation¹（聚合） diseases. Results from the research will appear online this week in the Proceedings² of the National Academy of Sciences.

 

In an earlier study of the muscle protein titin（肌联蛋白）, Rice chemist Peter Wolynes and his colleagues analyzed⁴ the likelihood of misfolding in proteins, in which domains⁶ -- discrete⁷ sections of a protein with independent folding characteristics -- become entangled⁸ with like sequences on nearby chains. They found the resulting molecular⁹ complexes called "dimers" were often unable to perform their functions and could become part of amyloid（含淀粉的） fibers¹⁰.

 

This time, Wolynes and his co-authors, Rice postdoctoral researcher Weihua Zheng and graduate student Nicholas Schafer, modeled constructs containing two, three or four identical titin domains. They discovered that rather than creating the linear connections others had studied in detail, these proteins aggregated¹¹ by branching; the proteins created structures that cross-linked with neighboring proteins and formed gel-like networks that resemble those that imbue¹²（灌输） spider silk with its remarkable¹³ flexibility¹⁴ and strength.

 

"We're asking with this investigation¹⁵, What happens after that first sticky contact forms?" Wolynes said. "What happens if we add more sticky molecules¹⁶? Does it continue to build up further structure out of that first contact?

 

"It turned out this protein we've been investigating has two amyloidogenic segments that allow for branch structures. That was a surprise," he said.

 

The researchers used their AWSEM (Associative memory, Water-mediated Structure and Energy Model) program to analyze³ how computer models of muscle proteins interact with each other, particularly in various temperatures that determine when a protein is likely to fold or unfold.

 

The program relies on Wolynes' groundbreaking principle of minimal¹⁷ frustration¹⁸ to determine how the energy associated with amino acids, bead-like elements in a monomer（单体） 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（粘性的） amyloid plaques¹⁹ often found in the brains of Alzheimer's patients.

 

The titin proteins the Rice team chose to study are not implicated²⁰ in disease but have been well-characterized by experimentalists; this gives the researchers a solid basis for comparison.

 

"In the real muscle protein, each domain⁵ 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.

点击收听单词发音