Stoichiometry and topology in protein folding.

A fundamental piece of the puzzle, that is the protein folding problem, refers to the balance between energetic and topological frustration. Energetic frustration results from the often conflicting requirements that hydrophobic residues need to reside inside the folded protein structure, while polar and charged residues prefer to reside on the surface of the structure in close contact with water. Moreover, even if the energetic frustration for a particular protein sequence is substantially minimized, the requirement of almost perfect solid-like packing for a protein structure leads to topological frustration manifested in conflicting geometrical orientation of the various parts of the sequence due to the chain connectivity. While topological frustration is relatively straightforward to study by reducing the protein chain to a homopolymeric description, understanding the origin and degree of energetic frustration in proteins is far more challenging.