Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115, USA.
Biochemistry. 2010 Aug 31;49(34):7323-43. doi: 10.1021/bi100588a.
The predicted structure and molecular trajectories from >80 ns molecular dynamics simulation of the solvated Double-Super Helix (DSH) model of nascent high-density lipoprotein (HDL) were determined and compared with experimental data on reconstituted nascent HDL obtained from multiple biophysical platforms, including small angle neutron scattering (SANS) with contrast variation, hydrogen-deuterium exchange tandem mass spectrometry (H/D-MS/MS), nuclear magnetic resonance spectroscopy (NMR), cross-linking tandem mass spectrometry (MS/MS), fluorescence resonance energy transfer (FRET), electron spin resonance spectroscopy (ESR), and electron microscopy. In general, biophysical constraints experimentally derived from the multiple platforms agree with the same quantities evaluated using the simulation trajectory. Notably, key structural features postulated for the recent DSH model of nascent HDL are retained during the simulation, including (1) the superhelical conformation of the antiparallel apolipoprotein A1 (apoA1) chains, (2) the lipid micellar-pseudolamellar organization, and (3) the solvent-exposed Solar Flare loops, proposed sites of interaction with LCAT (lecithin cholesteryl acyltransferase). Analysis of salt bridge persistence during simulation provides insights into structural features of apoA1 that forms the backbone of the lipoprotein. The combination of molecular dynamics simulation and experimental data from a broad range of biophysical platforms serves as a powerful approach to studying large macromolecular assemblies such as lipoproteins. This application to nascent HDL validates the DSH model proposed earlier and suggests new structural details of nascent HDL.
对水合双超螺旋（DSH）新生高密度脂蛋白（HDL）模型的 80 多纳秒分子动力学模拟的预测结构和分子轨迹进行了确定，并与来自多个生物物理平台的新生 HDL 重建实验数据进行了比较，这些平台包括小角中子散射（SANS）与对比变化、氢氘交换串联质谱（H/D-MS/MS）、核磁共振波谱（NMR）、交联串联质谱（MS/MS）、荧光共振能量转移（FRET）、电子自旋共振波谱（ESR）和电子显微镜。总的来说，从多个平台实验推导出的生物物理约束与使用模拟轨迹评估的相同数量一致。值得注意的是，新生 HDL 最近 DSH 模型中假定的关键结构特征在模拟过程中得以保留，包括（1）反向平行载脂蛋白 A1（apoA1）链的超螺旋构象，（2）脂质胶束-拟层状组织，以及（3）溶剂暴露的 Solar Flare 环，这是与 LCAT（卵磷脂胆固醇酰基转移酶）相互作用的假定位点。在模拟过程中对盐桥持久性的分析提供了对 apoA1 形成脂蛋白骨架的结构特征的深入了解。分子动力学模拟与来自广泛生物物理平台的实验数据的结合，为研究脂蛋白等大型大分子组装体提供了一种强大的方法。这种对新生 HDL 的应用验证了早先提出的 DSH 模型，并提出了新生 HDL 的新结构细节。
