Structural and dynamic features of apolipoprotein A-I cysteine mutants, Milano and Paris, in synthetic HDL

Pursuing an established research interest in our group, we built two models for synthetic HDL containing the natural cysteine mutants of apolipoprotein A-I, apolipoprotein A-I Milano (apoA-IM) and apolipoprotein A-I Paris (apoA-IP), both in their homodimeric form. Data on the structural and dynamic properties of such s-HDL are an essential preliminary step for the understanding of the biological activity of the two mutants. Furthermore, comparison between apoA-IM and apoA-IP allows evaluating the effects of the same mutation in a different position in the primary structure and to directly compare our findings with previously published models. We computed for 50 ns in explicit solvent the molecular dynamics of the two complexes and analyzed different properties as a function of time. The proposed s-HDL structures differ significantly from one another and from wild type apolipoprotein A-I. All features of the apoA-IM model are consistent with experimental data. The higher RMSF of apoA-IM has a counterpart in the finding that trypsin, matrix metalloproteases, and chymase degrade apoA-IM much faster than wild type apoA-I; the primary cutting site is correctly identified by molecular dynamics data on our model of apoA-IM-containing s-HDL. The few experimental data for apoA-IP prevent direct comparison with our findings.

Figure optionsDownload high-quality image (254 K)Download as PowerPoint slideResearch highlights▶ ApoA-I cystine mutants differ from wild type HDL in functional properties. ▶ Model building and dynamic evaluation of mutant HDL account for such differences. ▶ Experimental sensitivity to proteolysis is related to computed α-carbon fluctuations. ▶ Differential capacity to activate LCAT is related to varying helix registrations.