BAND 3 N-TERMINAL AA (10-16) AND DEOXY S POLYMERIZATION

脱氧血红蛋白的聚合与溶胶-凝胶转化 S将被一种未被探索的机制所抑制，在这种机制中， 血红蛋白分子的方法必须启动和 防止了聚合的扩散， 以保持功能完整。 氨基酸序列的肽 存在于人的带3的N-末端部分 红细胞与血红蛋白A在2，3-DPG受体处可逆结合 基因座 与脱氧构象的结合比与 羟考酮 这些肽深入到β-受体之间的空腔中， 根据长度的不同， 超出了四分体的范围。 之间的相互作用 条带3的N-末端胞质部分的片段， 血红蛋白S与血红蛋白A相当，但 这种肽对脱氧S聚合的影响还没有 被探索。 据推测，1）一个15个氨基酸的肽 的N-末端胞质结构域中相同的序列， 条带3将进入β链间区域，距离为18 并突出约27埃外 分子占据并封闭27埃的半球体积 β S链的2，3-DPG结合位点周围的半径和2） 肽的突出部分将通过纯粹的体积或通过 覆盖特定的相互作用部位，防止1-5埃的 表面β 6突变体和其他接触区域 引发聚合反应。 附加位阻 与血红蛋白S聚合物的形成可能源于1） C-末端10-12个残基中的β链和C-末端10- 12个残基中的β链。 A螺旋前的3个N-末端氨基酸（ 血红蛋白A的肽），和3）形成二元 脱氧血红蛋白S分子的复合物， β-对-β链并置的肽。 这些不能正确地 加入到聚合物中。 肽将被设计， 合成、纯化和表征：反应评价 将通过Csat、时间-粘度曲线、物理 凝胶的性质，P50，与其他聚阴离子的竞争性结合， 更换充电器和M.W. 结合性、可逆性和空间位阻 干扰将通过改变以下物质的摩尔比来优化： 肽与血红蛋白，肽长度，氨基酸序列， 轮廓 结果将提供新的数据成核， 聚合反应，以及聚合物和凝胶的结构。 一 将定义一类新的抑制剂， 在控制细胞内聚合基础方面的适用性 镰状细胞病的病理生理学和临床表现 紊乱

The polymerization and sol-gel transformation of deoxyhemoglobin S will be inhibited by an unexplored mechanism in which the close approach of hemoglobin molecules necessary to initiate and propagate polymerization is prevented and the hemoglobin is allowed to remain fully functional. Peptides of the amino acid sequence present in the N-terminal portion of Band 3 of the human erythrocyte bind reversibly to hemoglobin A at the 2,3-DPG receptor locus. Binding to the deoxy conformation is much greater than to the oxy. The peptides extend deep into the cavity between the beta chains and, depending on length, protrude for varying distances beyond the confines of the tetrad. The interactions between fragments of the N-terminal cytoplasmic portion of Band 3 and hemoglobin S are comparable with those of hemoglobin A but the effect of such peptides on the polymerization of deoxy S has not been explored. It is postulated that 1) a 15 amino acid peptide of the same sequences as in the N-terminal cytoplasmic domain of Band 3 will enter the inter-betaS chain region a distance of 18 angstrom and protrude approximately 27 angstrom outside the molecule to occupy and occlude a hemispheric volume of 27 angstrom radius around the 2,3-DPG binding site of the betaS chains and 2) the protruding portion of the peptide will, by sheer bulk or by covering up specific interacting sites, prevent the 1-5 angstrom approaches that the surface beta 6 mutant and other contact areas must make to initiate polymerization. Additional steric impedance to hemoglobin S polymer formation may arise from 1) disordering of the beta chains in the 10-12 residues f the C-termini and in the 3 N-terminal amino acids before the A helix (Changes induced in hemoglobin A by the peptide), and 3) the formation of binary complexes of deoxyhemoglobin S molecules tethered together by the peptide in beta-to-beta chain apposition. These could not properly incorporate into the polymer. The peptides will be designed, synthesized, purified, and characterized: evaluation of reactions with hemoglobin will be by Csat, time-viscosity profile, physical properties of gel, P50, competitive binding with other polyanions, change in charge and M.W. The binding, reversibility, and steric interference will be optimized by varying the molar rations of peptide to hemoglobin, peptide length, amino acid sequence, an contour. Results will provide new data on nucleation, the polymerization reaction, and the structure of polymer and gel. A new class of inhibitors will be defined that may ultimately find applicability in controlling the intracellular polymerization basic to the pathophysiology and clinical manifestations of sickle cell disorders.