Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
J Mol Graph Model. 2010 Nov;29(3):406-14. doi: 10.1016/j.jmgm.2010.08.002. Epub 2010 Aug 20.
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.
我们组一直致力于研究载脂蛋白 A-I 的天然半胱氨酸突变体，构建了两种含有天然半胱氨酸突变体的载脂蛋白 A-I 米兰（apoA-IM）和载脂蛋白 A-I 巴黎（apoA-IP）的人工 HDL 模型，这两种突变体均以同源二聚体的形式存在。关于这些 s-HDL 的结构和动态特性的数据是理解两种突变体的生物学活性的重要初步步骤。此外，apoA-IM 和 apoA-IP 的比较可以评估相同突变在一级结构中不同位置的影响，并直接将我们的发现与以前发表的模型进行比较。我们在明确的溶剂中对这两种复合物进行了 50ns 的分子动力学模拟，并随时间分析了不同的性质。所提出的 s-HDL 结构彼此之间以及与野生型载脂蛋白 A-I 有很大的不同。apoA-IM 模型的所有特征都与实验数据一致。apoA-IM 的 RMSF 较高，这与实验结果一致，即胰蛋白酶、基质金属蛋白酶和糜酶降解 apoA-IM 比野生型 apoA-I 快得多；分子动力学数据正确识别了 apoA-IM 模型的主要切割位点。apoA-IP 的少量实验数据限制了与我们的发现进行直接比较。
