Multiscale MD simulations of wild‐type and sickle hemoglobin aggregation

M. Olagunju, Jennifer Loschwitz, O. Olubiyi, B. Strodel
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引用次数: 1

Abstract

Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β‐globin chains of hemoglobin. This mutation gives rise to pathological aggregation of the sickle hemoglobin and, as a result, impaired oxygen binding, misshapen and short‐lived erythrocytes, and anemia. We aim to understand the structural effects caused by the single Glu6Val mutation leading to protein aggregation. To this end, we perform multiscale molecular dynamics simulations employing atomistic and coarse‐grained models of both wild‐type and sickle hemoglobin. We analyze the dynamics of hemoglobin monomers and dimers, study the aggregation of wild‐type and sickle hemoglobin into decamers, and analyze the protein–protein interactions in the resulting aggregates. We find that the aggregation of sickle hemoglobin is driven by both hydrophobic and electrostatic protein–protein interactions involving the mutation site and surrounding residues, leading to an extended interaction area and thus stable aggregates. The wild‐type protein can also self‐assemble, which, however, results from isolated interprotein salt bridges that do not yield stable aggregates. This knowledge can be exploited for the development of sickle hemoglobin‐aggregation inhibitors.
野生型和镰状血红蛋白聚集的多尺度MD模拟
镰状细胞病是一种血红蛋白病,由血红蛋白β -珠蛋白链6位谷氨酸突变为缬氨酸引起。这种突变引起镰状血红蛋白的病理性聚集,从而导致氧结合受损、红细胞畸形和短命以及贫血。我们的目的是了解单个Glu6Val突变导致蛋白质聚集所引起的结构效应。为此,我们采用原子和粗粒度模型对野生型和镰状血红蛋白进行多尺度分子动力学模拟。我们分析了血红蛋白单体和二聚体的动力学,研究了野生型和镰状血红蛋白成十聚体的聚集,并分析了由此产生的聚集中的蛋白质-蛋白质相互作用。我们发现镰状血红蛋白的聚集是由涉及突变位点和周围残基的疏水和静电蛋白质-蛋白质相互作用驱动的,导致相互作用区域扩大,从而形成稳定的聚集。野生型蛋白也可以自组装,然而,这是由于分离的蛋白间盐桥,不能产生稳定的聚集体。这些知识可以用于镰状血红蛋白聚集抑制剂的开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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