‘Inverse Melting’ and Folding of Temperature-Sensitive Mutant Proteins

Abstract

We discuss how the free energies of wild-type (normal) and mutant proteins can vary below the permissive temperature, and how ‘inverse melting’ behaviour may be possible if the mutant phase orders more quickly than the wild-type phase. Some interaction between mutant phase molecules will reduce the entropy of the mutant phase relative to the wild phase, and thus facilitate inverse melting. Excessive interaction between mutant phase molecules will likely cause them to aggregate, producing insoluble precipitates of mutant phase. We suggest that a folding protein molecule will be repelled away from three-dimensional configurations that host unstable dynamic modes, towards arrangements that support stable dynamic modes. Repulsion will be strongest when conditions for resonance are satisfied, and should accelerate attainment of the ultimate, folded configuration. Folding will be faster than estimated in Levinthal's paradox because configurations that are close to unstable dynamic modes are never properly sampled. Changes in the structure or environment of a protein molecule may alter its resonances and so result in a different (mis)folded final structure.