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Atomistic simulations of heme dissociation pathways in human methemoglobins reveal hidden intermediates.
Biochemistry ( IF 2.9 ) Pub Date : 2020-09-18 , DOI: 10.1021/acs.biochem.0c00607
Premila P Samuel 1 , David A Case 1, 2
Affiliation  

Heme dissociations disrupt function and structural integrity of human hemoglobin and trigger various cardiovascular complications. These events become significant in methemoglobins that have undergone autoxidation of ferrous into ferric heme. We have structurally characterized the heme disassociation pathways for adult tetrameric methemoglobins using all-atom molecular dynamics simulations. These reveal that bis-histidine hemichromes, characterized here by the coordination of heme iron to both the F8 (proximal) and E7 (distal) histidines, are seen as intermediates following dissociation of the water molecule distally bound to each heme iron. Later, the breaking of coordination between heme iron and proximal histidine disrupts the F helix and pushes it away from the heme cavity, enabling both bulk solvent penetration and disruption of tetramer interface interactions. The interactions inhibiting heme dissociation were then seen to be (i) either a direct or a water-molecule-mediated interaction between distal histidine and heme iron and (ii) stacking between heme and the αCE1/βCD1 phenylalanine residue. These interactions are less important in the β than in α subunits due to a more flexible β subunit CE loop region. The absence of a distal histidine interaction in the H(E7)L mutant and increased heme cavity volume in the V(E11)A mutant both promoted heme escape from the protein interior. Adult and fetal hemoglobins were seen to share a general heme disassociation pathway and intermediates due to the conservation of key heme pocket residues. The intermediates seen here are analyzed in light of experimental studies of heme dissociation and pathways of certain hemoglobinopathies.

中文翻译:

人类高铁血红蛋白中血红素解离途径的原子模拟揭示了隐藏的中间体。

血红素解离破坏人类血红蛋白的功能和结构完整性,并引发各种心血管并发症。这些事件在经过亚铁自氧化成三价铁血红素的高铁血红蛋白中变得重要。我们使用全原子分子动力学模拟对成人四聚体高铁血红蛋白的血红素解离途径进行了结构表征。这些表明双组氨酸半色素,其特征是血红素铁与 F8(近端)和 E7(远端)组氨酸的配位,被视为与每个血红素铁远端结合的水分子解离后的中间体。后来,血红素铁和近端组氨酸之间协调的断裂破坏了 F 螺旋并将其推离血红素腔,使大量溶剂渗透和四聚体界面相互作用的破坏成为可能。抑制血红素解离的相互作用被认为是 (i) 远端组氨酸和血红素铁之间的直接或水分子介导的相互作用,以及 (ii) 血红素和 αCE1/βCD1 苯丙氨酸残基之间的堆积。由于更灵活的 β 亚基 CE 环区域,这些相互作用在 β 亚基中不如在 α 亚基中重要。H(E7)L 突变体中远端组氨酸相互作用的缺失和 V(E11)A 突变体中血红素腔体积的增加都促进了血红素从蛋白质内部逃逸。由于关键血红素口袋残基的保护,成人和胎儿血红蛋白被认为共享一般的血红素解离途径和中间体。
更新日期:2020-10-28
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