Stoichiometry and Topology in Protein Folding

Ruxandra I. Dima
2011 Journal of Biomolecular Structure and Dynamics  
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
more » ... ized, 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. Mittal et al.'s study (1) addresses the energetics of the protein folding problem and therefore the energetic frustration issue (2). Starting from a large and diverse set of protein structures present in the PDB (3), the authors aim to uncover the driving force between the formation of amino acid pairs in functional protein states: is it the stoichiometry or the chemistry (mainly the hydrophobicity) of the members? Their study lands in the middle of a long standing controversy in the protein folding field that started with Kauzmann's 1959 review in which the author argued that the stabilization of a protein structure is largely due to the hydrophobic effect (4). By contrast, according to this view, hydrogen bonds have little or maybe even opposing influence on the protein folding reaction. While this is still an influential point of view, alternative proposals are gaining ground. Recent experimental findings and theoretical modeling indicate that osmolytes, which can dramatically influence the folding/unfolding processes, target primarily the protein backbone (not the side-chains) and act on the unfolded state rather than on the native state (5, 6), and that most mesophilic proteins unfold or fold under very similar denaturating/renaturating conditions (temperature or chemical denaturation) (7). It is also now well known that the number of stable domains is limited. Recently, Rose and collaborators (8) showed that two-state folding implies that conformation and stability are separable. Based on these findings, as well as the success of the tube-like model of proteins (9, 10) in proving that the native conformations of proteins can emerge on the basis of geometry and symmetry, the view that hydrogen bonding, rather than hydrophobicity, plays the central role in the protein folding process received an unprecedented push (8). According to this viewpoint, "side chains serve to select conformations from the limited repertoire of possible backbone conformations: alpha-helix, beta-strand, turns, and loops." This viewpoint puts special emphasis on the protein backbone for the protein folding process resulting in the proposal that water is a poor solvent for the protein backbone. This proposal received backing from a study of intrinsically disordered proteins (11)
doi:10.1080/073911011010524964 pmid:21142235 fatcat:oa5ipazio5cbhpftpjuwwb5eee