title: Structural and dynamic features of apolipoprotein A-I cysteine mutants, Milano and Paris, in synthetic HDL.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Alessandro Guerini
authors.initials: AG
authors.lastname: Rocco
authors.forename: Cristina
authors.initials: C
authors.lastname: Sensi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gianazza
authors.forename: Laura
authors.initials: L
authors.lastname: Calabresi
authors.forename: Guido
authors.initials: G
authors.lastname: Franceschini
authors.forename: Cesare R
authors.initials: CR
authors.lastname: Sirtori
authors.forename: Ivano
authors.initials: I
authors.lastname: Eberini
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000235:genetics*; D019281:Dimerization; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012997:Solvents / Q000737:chemistry
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D012997:Solvents; C080631:apolipoprotein A-I Milano; C405602:apolipoprotein A-I Paris; D003545:Cysteine