A model structure for the heterodimer apoA-I_Milano-- apoA-II supports its peculiar susceptibility to proteolysis

¹ Università degli Studi di Milano
² Dulbecco Telethon Institute

^* To whom correspondence should be addressed. E-mail: ivano.eberini{at}unimi.it.

Submitted on March 27, 2006
Revised on April 12, 2006
Accepted on 19 July 2006

	Abstract

In the present 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 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 RMSF 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.

Key Words: apolipoprotein A-I Milano, apolipoprotein A-II, molecular docking, molecular dynamics, phospholipids, synthetic HDL

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