 Initially, Frank proposed that the cyclol form might be stabilized by better interactions with the surrounding solvent; later, Wrinch and Irving Langmuir hypothesized that hydrophobic association of nonpolar sidechains provides stabilizing energy to overcome the energetic cost of the cyclol reactions.The lability of the cyclol bond was seen as an "advantage" of the model, since it provided a natural explanation for the properties of denaturation; reversion of cyclol bonds to their more stable amide form would open up the structure and allows those bonds to be attacked by proteases, consistent with experiment.Early studies showed that proteins denatured by pressure are often in a different state than the same proteins denatured by high temperature, which was interpreted as possibly supporting the cyclol model of denaturation.