From propensities to patterns to principles in protein folding

As proposed here, β-turns play an essential role in protein self-assembly. This compact, four-residue motif affects protein conformation dramatically by reversing the overall chain direction. Turns are the "hinges" in globular proteins. This new proposal broadens a previous hypothesis that globular proteins solve the folding problem in part by filtering conformers with unsatisfied backbone hydrogen bonds, thereby preorganizing the folding population. Recapitulating that hypothesis: unsatisfied conformers would be dramatically destabilizing, shifting the U(nfolded) ⇌ N(ative) equilibrium far to the left. If even a single backbone polar group is satisfied by solvent when unfolded but buried and unsatisfied when folded, that energy penalty alone, approximately +5 kcal/mol, would rival almost the entire free energy of protein stabilization at room temperature. Consequently, globular proteins are built on scaffolds of hydrogen-bonded α-helices and/or strands of β-sheet, motifs that can be extended indefinitely, with intra-segment hydrogen bond partners for their backbone polar groups and without steric clash. Scaffolds foster a protein-wide hydrogen-bonded network, and, of thermodynamic necessity, they self-assemble cooperatively. Unlike elements of repetitive secondary structure, α-helices and β-sheet, a four-residue β-turn has only a single hydrogen bond (from i + 3 → i), not a cooperatively formed assembly of hydrogen bonds. As such, turns can form autonomously and are poised to initiate assembly of scaffold elements by bringing them together in an orientation and registration that promotes cooperative "zipping". The overall effect of this self-assembly mechanism is to induce substantial preorganization in the thermodynamically accessible folding population and, concomitantly, to reduce the folding entropy.