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

Department of Biochemistry, University of Connecticut Health Center, Farmington, Connecticut 06030, USA

Reprint requests to: Zheng-yu Peng, MC-3305, Department of Biochemistry, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA; e-mail: peng{at}sun.uchc.edu; fax: 860-679-3408.

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 -lactalbumin (-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 -LA molten globule, which takes into consideration the dynamic nature of this partially folded species.

Keywords: -Lactalbumin; molten globule; effective concentration; side-chain interaction; double-mutant cycle analysis; protein folding

Abbreviations: -LA, -lactalbumin • -LA-[28–111], a single disulfide variant of human -LA in which all cysteines except for Cys28 and Cys111 were replaced by alanine • C_eff, effective concentration • CD, circular dichroism • NMR, nuclear magnetic resonance • HPLC, high-performance liquid chromatography.

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