It takes a lot more than several amino acids joined together to obtain a functional protein. Just as an origami figure, proteins need to fold into 3D shapes in order to function. But while a polypeptide chain could literally spend more time than the age of the universe trying all of its possible conformations, it opts for one and not any other and in no more than a few seconds. How proteins achieve this remains one of the major unsolved questions in the history of biochemistry.
Figuring out the so-called “protein folding problem” not only will allow researchers to predict the structure of any protein based purely on its amino acid sequence but also to understand the relationship between structure and function.
Moreover, it’ll fuel the design of new proteins and enzymes with extremely high specificity for their biological targets. But how close is this puzzle to being solved?
In 1961, Nobel laureate Christian Anfinsen gave the first clues to solve this mystery of how proteins behave. He discovered that within the sequence of amino acids, there existed instructions on how to fold a protein in 3D. By mixing mercaptoethanol and urea, a case protein changed from a 3D structure to a long stretched chain. But when the environmental conditions were restored, voila!, the protein went back to its original shape and recovered its activity. This result led Anfinsen to conclude that the protein’s own sequence is all that a protein needs for its correct folding.
Up to now, there’s no general agreement on how all proteins fold. However, researchers do know that polypeptide chains of amino acids (primary structure) fold into helices and strands of sheet (secondary structure), which in turn assemble to give proteins their intricate 3D shapes and folding patterns (tertiary structure).
Quite a bit of information about protein folding has been uncovered since Anfinsen’s landmark experiment and a significant milestone actually came up at last year’s Critical Assessment of Structure Prediction (CASP) competition. In an unprecedented and stunning win, Google-affiliated artificial intelligence (AI) research lab DeepMind, performed protein structure predictions far more accurate than any that have come before, demonstrating that AI can be a great tool to potentially unlock the folding mystery.
What any protein can do depends on its unique 3D structure, which makes predicting and understanding how a protein folds even more important.
Let the mystery unfold!