 Model of lacI monomer used in protein folding simulations. Picture: Rice University
Nature
refuses to choose between form and function when it comes to protein
folding; each protein's function is directly related to its shape, and
when proteins misfold – something that's known to occur in a number of
diseases like Alzheimer's and Huntington's – they don't function as
they should.
In the new study, scientists designed and tested
a new computational approach that aimed to study proteins with known
shapes in order to ascertain which of their parts were the most stable
in the face of chemical and thermal fluctuations.
"We found
that the most stable parts of the final, folded protein come together
first during the folding," said co-author Pernilla Wittung-Stafshede,
associate professor of biochemistry and cell biology and of chemistry.
She said the findings could help both scientists who are attempting to
design synthetic proteins with a particular shape and scientists who
are attempting to associate the shape and function of naturally
occurring proteins.
The computational approach tested in the
experiment was developed by the research group of co-author Jianpeng
Ma, associate professor of bioengineering at Rice and associate
professor of biochemistry and molecular biology at Baylor College of
Medicine. Ma's group, which mainly focuses on multi-scale protein
structure modeling and prediction, developed highly accurate
knowledge-based potential functions that made the current collaborative
study possible.
"As far as we know, no one has ever used this
type of knowledge-based, statistical approach to predict the stability
cores of proteins," Ma said. "Our results suggest that thermodynamics
and kinetics are closely correlated in proteins and appear to have
co-evolved for optimizing both the folding rate and the stability of
proteins."
Wittung-Stafshede's group, which specializes in
experimental studies related to protein folding, tested the model's
predictions against experimental data gathered for several forms of the
protein azurin, a copper-containing protein that folds into a
sandwich-like structure called a beta sheet, which is a common fold in
nature that consists of two beta-sheets of amino-acid strands meshed
together.
"In folding study the right combination of expertise
in computational and experimental approaches is vital for success," Ma
said. "Our collaborative team has set an excellent example for future
study."
Relare Links:
Rice University, Department of Biochemistry and Cell Biology .
Pernilla Wittung-Stafshede web page .
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