Protein folding: a problem with multiple solutions.

There is continued interest in predicting the structure of proteins either at the simplest level of identifying their fold class or persevering all the way to an atomic resolution structure. Protein folding methods have become very sophisticated and many successes have been recorded with claims to have solved the native structure of the protein. But for any given protein, there may be more than one solution. Many proteins can exist in one of the other two (or more) different forms and some populate multiple metastable states. Here, the two-state case is considered and the key structural changes that take place when the protein switches from one state to the other are identified. Analysis of these results show that hydrogen bonding patterns and hydrophobic contacts vary considerably between different conformers. Contrary to what has often been assumed previously, these two types of interaction operate essentially independently of one another. Core packing is critical for proper protein structure and function and it is shown that there are considerable changes in internal cavity volumes in many cases. The way in which these switches are made is fold dependent. Considerations such as these need to be taken into account in protein structure prediction.