A model of dynamic side‐chain–side‐chain interactions in the α‐lactalbumin molten globule

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Abstract
Proteins in the molten globule state contain high levels of secondary structure, as well as a rudimentary, nativelike tertiary topology. Thus, the structural similarity between the molten globule and native proteins may have a significant bearing in understanding the protein‐folding problem. To explore the nature of side‐chain–side‐chain interactions in the α‐lactalbumin (α‐LA) molten globule, we determined the effective concentration for formation of the 28–111 disulfide bond in 14 double‐mutant proteins, each containing two hydrophobic core residues replaced by alanine. We compared our results with those of single‐alanine substitutions using the framework of double‐mutant cycle analysis and found that, in the majority of cases, the effects of two alanine substitutions are additive. Based on these results, we propose a model of side‐chain–side‐chain interactions in the α‐LA molten globule, which takes into consideration the dynamic nature of this partially folded species.