The basic mechanisms of infonnation transfer from DNA to RNA (transcrip tion) and from RNA to proteins (translation) are understood at least in outline. In contrast, understanding the transfer of information from one dimension to three dimensions (ie protein folding) remains as a major unsolved problem in modem molecular biology.

For small, single-domain proteins. the protein folding problem can be reduced to one of physical chemistry. whereby a unique conformation of a precisely defined solute (the polypeptide chain) is obtained when it is placed in a defined solvent (aqueous buffer) in the absence of other cofactors or catalysts. Theoretical attempts to model the protein folding process from first principles are, however, severely hindered because of the enonnous number of competing interactions to consider, and because the difference in free energy between the folded and unfolded states is a tiny fraction of the energies favoring and opposing folding: the calculations must necessarily be very accurate.