Myths and verities in protein folding theories: from Frank and Evans iceberg-conjecture to explanation of the hydrophobic effect.

Starting from the seminal article by Frank and Evans where the "iceberg formation" idea was first expressed, we follow the evolution of this idea to the explanation of the hydrophobic effect. We show that the idea of iceberg formation can provide an explanation to the entropy, and enthalpy of solvation of non-polar solutes in water, provided one first explains why a simple non-polar solute would form icebergs in the first place. Having done that, the questions regarding the outstanding large hydrophobic solvation Gibbs energy remains unexplained. This conclusion follows from the exact entropy-enthalpy-compensation pertaining to any structural changes induced in the solvent. We also comment on some misinterpretation of the partial molar heat capacity of non-polar solutes in water.