Malajczuk Chris J, Gandhi Neha S, Mancera Ricardo L
School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute and Curtin Institute for Computation, Curtin University, GPO Box U1987, Perth, WA 6845, Australia.
School of Mathematical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4000, Australia.
J Struct Biol X. 2020 Dec 10;5:100042. doi: 10.1016/j.yjsbx.2020.100042. eCollection 2021.
Human serum high-density lipoproteins (HDLs) are a population of small, dense protein-lipid aggregates that are crucial for intravascular lipid trafficking and are protective against cardiovascular disease. The spheroidal HDL subfraction can be separated by size and density into five major subpopulations with distinct molecular compositions and unique biological functionalities: HDL, HDL, HDL, HDL and HDL. Representative molecular models of these five subpopulations were developed and characterised for the first time in the presence of multiple copies of its primary protein component apolipoprotein A-I (apoA-I) using coarse-grained molecular dynamics simulations. Each HDL model exhibited size, morphological and compositional profiles consistent with experimental observables. With increasing particle size the separation of core and surface molecules became progressively more defined, resulting in enhanced core lipid mixing, reduced core lipid exposure at the surface, and the formation of an interstitial region between core and surface molecules in HDL. Cholesterol molecules tended to localise around the central helix-5 of apoA-I, whilst triglyceride molecules predominantly interacted with aromatic, hydrophobic residues located within the terminal helix-10 across all subpopulation models. The three intermediate HDL models exhibited similar surface profiles despite having distinct molecular compositions. ApoA-I in trefoil, quatrefoil and pentafoil arrangements across the surface of HDL particles exhibited significant warping and twisting, but largely retained intermolecular contacts between adjacent apoA-I chains. Representative HDL subpopulations differed in particle size, morphology, intermolecular interaction profiles and lipid and protein dynamics. These findings reveal how different HDL subpopulations might exhibit distinct functional associations depending on particle size, form and composition.
人血清高密度脂蛋白（HDL）是一群小而致密的蛋白质 - 脂质聚集体，对血管内脂质运输至关重要，并且对心血管疾病具有保护作用。球形HDL亚组分可根据大小和密度分为五个主要亚群，它们具有不同的分子组成和独特的生物学功能：HDL、HDL、HDL、HDL和HDL。首次使用粗粒度分子动力学模拟，在其主要蛋白质成分载脂蛋白A - I（apoA - I）的多个拷贝存在的情况下，开发并表征了这五个亚群的代表性分子模型。每个HDL模型都呈现出与实验观测结果一致的大小、形态和组成特征。随着粒径的增加，核心分子和表面分子的分离逐渐变得更加明显，导致核心脂质混合增强，核心脂质在表面的暴露减少，并且在HDL的核心和表面分子之间形成了一个间隙区域。胆固醇分子倾向于定位在apoA - I的中央螺旋 - 5周围，而甘油三酯分子在所有亚群模型中主要与位于末端螺旋 - 10内的芳香族疏水残基相互作用。尽管具有不同的分子组成，但三个中间HDL模型呈现出相似的表面特征。HDL颗粒表面呈三叶、四叶和五叶排列的apoA - I表现出明显的翘曲和扭曲，但在很大程度上保留了相邻apoA - I链之间的分子间接触。代表性的HDL亚群在粒径、形态、分子间相互作用特征以及脂质和蛋白质动力学方面存在差异。这些发现揭示了不同的HDL亚群如何根据颗粒大小、形式和组成表现出不同的功能关联。
