Abstract：
The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptors (LDLR). Gain-of-function (GOF) variants of PCSK9 significantly affects lipid metabolism leading to coronary artery disease (CAD), owing to the raising the plasma low-density lipoprotein (LDL). Considering the public health matter, large-scale genomic studies have been conducted worldwide to provide the genetic architecture of populations for the implementation of precision medicine actions. Nevertheless, despite the advances in genomic studies, non-European populations are still underrepresented in public genomic data banks. Despite this, we found two high-frequency variants (rs505151 and rs562556) in the ABraOM databank (Brazilian genomic variants) from a cohort SABE study conducted in the largest city of Brazil, São Paulo. Here, we assessed the structural and dynamical features of these variants against WT through a molecular dynamics study. We sought fundamental dynamical interdomain relations through Perturb Response Scanning (PRS) and we found an interesting change of dynamical relation between prodomain and Cysteine-Histidine-Rich-Domain (CHRD) in the variants. The results highlight the pivotal role of prodomain in the PCSK9 dynamic and the implications for the development of new drugs depending on patient group genotype.
摘要：
前蛋白转化酶枯草杆菌蛋白酶/Kexin9型（PCSK9）促进低密度脂蛋白受体（LDLR）的降解。PCSK9的功能增益（GOF）变体显着影响脂质代谢，导致冠状动脉疾病（CAD），由于血浆低密度脂蛋白（LDL）升高。考虑到公共卫生问题，在全球范围内进行了大规模的基因组研究，为实施精准医疗行动提供了人群的遗传结构。然而，尽管基因组研究取得了进展，非欧洲人群在公共基因组数据库中的代表性仍然不足.尽管如此,我们在ABraOM数据库（巴西基因组变异）中发现了两个高频变异（rs505151和rs562556），来自在巴西最大城市进行的SABE队列研究，圣保罗.这里,我们通过分子动力学研究评估了这些变异体对WT的结构和动力学特征.我们通过微扰响应扫描（PRS）寻求基本的动态域间关系，并且发现了变体中前结构域和半胱氨酸-组氨酸-丰富结构域（CHRD）之间的动态关系的有趣变化。结果强调了前结构域在PCSK9动态中的关键作用以及取决于患者组基因型的新药开发的意义。
