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A Model Structure for the Heterodimer apoA-I_Milano–apoA-II Supports Its Peculiar Susceptibility to Proteolysis

Alessandro Guerini Rocco ^*, Luca Mollica , Elisabetta Gianazza ^*, Laura Calabresi , Guido Franceschini , Cesare R. Sirtori ^*  and Ivano Eberini ^*

^* Gruppo di Studio per la Proteomica e la Struttura delle Proteine, Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Milan, Italy; and Dulbecco Telethon Institute c/o S. Raffaele Scientific Institute, Biomolecular NMR Laboratory, Milan, Italy

Correspondence: Address reprint requests to Ivano Eberini, Tel.: 39-02-5051-8395; E-mail: ivano.eberini{at}unimi.it.

In this study, we propose a structure for the heterodimer between apolipoprotein A-I_Milano and apolipoprotein A-II (apoA-I_M–apoA-II) in a synthetic high-density lipoprotein (HDL) containing L--palmitoyloleoyl phosphatidylcholine. We applied bioinformatics/computational tools and procedures, such as molecular docking, molecular and essential dynamics, starting from published crystal structures for apolipoprotein A-I and apolipoprotein A-II. Structural and energetic analyses onto the simulated system showed that the molecular dynamics produced a stabilized synthetic HDL. The essential dynamic analysis showed a deviation from the starting belt structure. Our structural results were validated by limited proteolysis experiments on HDL from apoA-I_M carriers in comparison with control HDL. The high sensitivity of apoA-I_M–apoA-II to proteases was in agreement with the high root mean-square fluctuation values and the reduction in secondary structure content from molecular dynamics data. Circular dichroism on synthetic HDL containing apoA-I_M–apoA-II was consistent with the -helix content computed on the proposed model.

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