The Information for Protein Folding Is Encoded in the Sequence

Any polypeptide chain containing n residues could, in principle, fold into 8n conformations. This value is based on the fact that only eight bond angles are stereochemically allowed in the polypeptide backbone. In general, however, all molecules of any protein species adopt a single conformation, called the native state; for the vast majority of proteins, the native state is the most stably folded form of the molecule.

What guides proteins to their native folded state? The answer to this question initially came from in vitro studies on protein refolding. Thermal energy from heat, extremes of pH that alter the charges on amino acid side chains, and chemicals such as urea or guanidine hydrochloride at concentrations of 6-8 M can disrupt the weak noncovalent interactions that stabilize the native conformation of a protein. The denaturation resulting from such treatment causes a protein to lose both its native conformation and its biological activity.

Many proteins that are completely unfolded in 8 M urea and p-mercaptoethanol (which reduces disulfide bonds) spontaneously renature (refold) into their native states when the denaturing reagents are removed by dialysis. Because no cofactors or other proteins are required, in vitro protein folding is a self-directed process. In other words, sufficient information must be contained in the protein's primary sequence to direct correct refolding. The observed similarity in the folded, three-dimensional structures of proteins with similar amino acid sequences, noted in Section 3.1, provided other evidence that the primary sequence also determines protein folding in vivo.

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