Short-Range Contact Preferences and Long-Range Indifference: Is Protein Folding Stoichiometry Driven?

Abstract

Mittal et al. (1) recently advanced an unconventional view on protein folding. By analyzing the spatial neighborhoods of amino acid residues in an extensive set of structures in the Protein Data Bank (PDB), the authors concluded that preferential interactions between amino acid residues do not drive protein folding. In this connection, it should be noted that preferential interactions between amino acids are the basis for introducing knowledge-based potentials, which in turn provide the underpinning for present day three-dimensional protein structure prediction by modeling and simulation (2-5 and references therein). Instead of these preferential interactions, Mittal et al. indicate that “protein folding is a direct consequence of a narrow band of stoichiometric occurrences of amino-acids in the primary sequences” (1). According to the authors, this observation is akin to Chargaff’s discovery that the molar ratios of adenine and thymine and that of guanine and cytosine in DNA were not far from unity (6).