Protection against the exchange of backbone amide hydrogens (NH) with solvent hydrogens in globular proteins provides remarkable insight into the structures of the rare high-energy states that populate their free-energy surfaces for folding. However, a unified theory to rationalize these high-energy states in terms of the structure and sequence of the resident proteins has been lacking. The branched aliphatic side chain (BASiC) hypothesis has been proposed to explain the protection pattern observed in a pair of TIM barrel proteins. The hypothesis postulates that the side chains of isoleucine, leucine, and valine (ILV) residues generally form large hydrophobic clusters that are very effective at preventing water from penetrating the hydrogen-bonding network beneath them, thereby enhancing the ability of solvent exchange protection of. The link between secondary and tertiary structure enables these ILV clusters to serve as stable cores in the energetic partially folded state. The statistically significant correlation between the position of large ILV clusters in the native conformation and the robust conservation of various motif exchanges reported in the literature supports the generality of the BASiC hypothesis. The results also illustrate the need to elaborate on this simple hypothesis to explain the role of adjacent hydrocarbon moieties in defining the stable core of the partially folded state along the folding reaction coordinates.
It has been more than 50 years since Walter Kauzmann published his seminal review of protein denaturation reactions. 1 His analysis of the various factors involved in stabilizing the native conformation of proteins predicted an important role for hydrophobic effects and hydrogen bonding. Based on solubility data for nonpolar analogs of side chains and the propensity of detergents and organic solvents to denature proteins, he reasoned that aliphatic and aromatic side chains would be preferentially sequestered inside proteins. Denaturation of proteins by guanidine hydrochloride and urea (analogues of peptide bonds) was considered evidence for an important contribution of backbone-backbone hydrogen bonds. His idea was confirmed shortly thereafter when the first crystal structure of the protein, myoglobin, appeared. 2 Although ensuing vigorous debate over the relative importance of hydrophobic effects and hydrogen bonding for stability,3,4,5,6 it is generally accepted that buried and closely packed non-polar side chains are essential for stabilizing globular proteins for their natural function Form matters. valine structure
