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A protein dissection study demonstrates that two specific hydrophobic clusters play a key role in stabilizing the core structure of the molten globule state of human α‐lactalbumin

The molten globule state of α‐lactalbumin (αLA) has served as a paradigm for understanding the role of these partially folded states in protein folding. We previously showed that a peptide construct consisting of the A and B helices (residues 1–38) cross‐linked to the D‐ and C‐terminal 310 helices (residues 101–120) of αLA is capable of folding to a stable molten globule‐like state. Here, we report the study of three peptide constructs that are designed to investigate the contribution two short hydrophobic sequences located near the C‐terminus of αLA make to the structure and stability of the αLA molten globule state. These regions of the protein have been shown to form stable non‐native structures in isolation. The three peptide constructs contain residues 1–38 cross‐linked to three separate C‐terminal peptides via the native 28–111 disulfide bond. The C‐terminal peptides consist of residues 101–114, 106–120, and 106–114. The results of CD, fluorescence, ANS binding, and urea denaturation experiments indicate that constructs that lack either of the hydrophobic sequences (residues 101–105 and 115–120) are significantly less structured. These results highlight the importance of long‐range, mutually stabilizing interactions within the molten globule state of the protein. Proteins 2001;42:237–242. © 2000 Wiley‐Liss, Inc.