THE NATIVE-LIKE TERTIARY FOLD IN MOLTEN GLOBULE ALPHA-LACTALBUMIN APPEARS TO BE CONTROLLED BY A CONTINUOUS-PHASE TRANSITION

On account of its ability to discriminate between secondary, loop and sidegroup structure and its special sensitivity to conformational mobi lity, vibrational Raman optical activity (ROA) has provided new insigh ts into the complexity of order within the molten globule state from m easurements on alpha-lactalbumin at pH 2.0 over the temperature range 2 to 45 degrees C. Thus while much of the secondary structure present in the native protein persists with only a small gradual decrease with increasing temperature, the tertiary backbone fold changes dramatical ly, being almost complete and native-like at 2 degrees C and almost co mpletely disordered at 35 degrees C. The change of the tertiary fold w ith temperature is cooperati ire but has no latent heat, and so has th e approximate characteristics of a continuous phase transition, being of the order-disorder type since it involves the interconversion of ri gid, locally-ordered loop structure with disordered mobile backbone st ructure. This has implications for protein folding because the long-ra nge correlations that exist in the critical region of a continuous (bu t not in a first-order) phase transition could resolve, in principle, the problem of how the protein finds its native-like folding pattern a t the molten globule stage. (C) 1996 Academic Press Limited.