Proof of how proteins fold into the right structure

A protein not only has a special sequence of amino acids, it also needs to have the right folded structure in order to function as it should in the body. An international study led by Per Jemth at Uppsala University now shows how this folding occurs. The findings, published in this week's Web edition of Proceedings of the National Academy of Sciences, PNAS, constitute experimental proof of an existing theory and provide key knowledge of the connection between the structure and folding of proteins.

Proteins govern most processes in all living organisms and consist of long chains of linked amino acids. But for proteins to function, they need to be folded into their functional three-dimensional form, which is determined by their sequence of amino acids.

One question that has long occupied protein chemists is how this protein folding occurs and how it can happen so rapidly, considering the innumerable incorrect forms that a long chain of amino acids might assume. Theoretical chemists have developed a theory of an ‘energy landscape' that enables an amino-acid chain to rapidly find its most stable form, that is, the proper functional structure. The theory predicts that an unfolded amino-acid chain has a relatively open and flat energy landscape, so that the chain can assume many different shapes. But the landscape quickly leads the amino-acid chain to areas that limit the forms the chain can assume and only allows those that are similar to the final functional form, the native state.

"The closer the amino-acid chain gets to its final form, the more tightly regulated the folding reaction is, according to the theory," says Per Jemth, who directed the study together with Michele Vendruscolo in Cambridge and Stefano Gianni in Rome.

There is previous experimental data that squares well with the notion of an energy landscape, but the evidence has often been indirect. In the current study, where experiments were combined with computer simulations that produce atomic resolution images of how the protein folds, the scientists studied two related proteins that have the same final shape, but different sequences of amino acids. The findings constitute experimental proof of the theory.

The researchers show how the two proteins initially follow different folding routes, become more similar to each other in the course of the reaction, and finally meet in their native shape. The computer simulations show how the protein can enter dead ends at first, or take unnecessary detours, by building temporary forms that are then undone so the protein get back on track.

"The folding route has many alternatives initially but is strictly limited by the protein's native state toward the end," says PhD student Celestine Chi, who  conducted the experimental work in collaboration with his colleague Nicoletta Calosci.

"The findings were expected in a sense, but it was not self-evident just how this could be demonstrated experimentally."

The study is a collaborative effort involving Uppsala University, the University of Cambridge and Università di Roma "La Sapienza."

Read the article on PNAS website.

For more information, please contact Per Jemth at phone: +46 (0)18-471 45 57; cell phone: +46 (0)70-260 51 92; or per.jemth@imbim.uu.se