Role of charge and hydrophobicity in liprotide formation: a molecular dynamics study with experimental constraints

Jannik Nedergaard Pedersen, Pim Wilhelmus Johannes Maria Frederix, Jan Skov Pedersen, Siewert Jan Marrink, Daniel Otzen

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Bovine α-lactalbumin (aLA) and oleate (OA) form a complex that has been intensively studied for its tumoricidal activity. Small-angle X-ray scattering (SAXS) has revealed a lipid core surrounded by partially unfolded protein. We call this type of complex a liprotide. Little is known of the molecular interactions between OA and aLA and no technique has so far provided any high resolution structure of liprotides. Here, we used coarse grained (CG) molecular dynamics (MD) simulations, Isothermal titration calorimetry (ITC) and SAXS to investigate the interactions between aLA and OA during the process of liprotide formation. By using ITC we found that the strongest enthalpic interactions occurred at a molar ratio of 12.0 ± 1.4 OA/aLA. Liprotides formed between OA and aLA at several OA/aLA ratios in silico were stable in both CG and all-atom simulations. We have calculated SAXS spectra from the simulated structures which show good agreement with experimentally measured patterns of matching liprotides. The simulations showed that aLA assumes a molten globular (MG) state, exposing several hydrophobic patches involved in interactions with OA. Initial binding of aLA to OA occurs in an area of aLA where a high amount of positive charge is located and only later hydrophobic interactions become important. Our findings suggest a general mechanism for liprotide formation and may explain the ability of a large number of proteins to form liprotides with OA.

Original languageEnglish
Pages (from-to)263–271
Number of pages9
Publication statusPublished - 2 Feb 2018


  • Journal Article


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