DYNAMICS OF PROTEINS AND STUDIES ON SICKLE CELL DISEASE

蛋白质动力学和镰状细胞病研究

• 批准号: 3754169
• 负责人: W A EATON
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3754169
• 关键词: biophysics; blood disorder chemotherapy; chemical binding; chemical kinetics; chemical models; computer simulation; conformation; cytochrome c; hemoglobin; hemoglobin Ss; hemoprotein structure; hydroxyurea; laser spectrometry; light scattering; molecular dynamics; myoglobin; photochemistry; photolysis; polymerization; protein folding; protein structure function; sickle cell anemia; sickling inhibitor; time resolved data

Time resolved optical spectroscopy in photodissociation experiments and molecular dynamics simulations are being used to investigate protein folding and structure function relations in heme proteins. Fast events in the folding of cytochrome c are being studied by optically triggering the folding reaction with nanosecond laser pulses. Before folding begins transient binding of both non-native and native ligands from the unfolded polypeptide has been observed on a microsecond time scale. We have confirmed the prediction from our previous studies on the viscosity dependence of the conformational relaxation in myoglobin that the low temperature behavior of myoglobin with a "frozen" distribution of conformational substates can be mimicked in a room temperature glass, including the observation of a wide distribution of geminate rebinding rates and spectral changes caused by kinetic hole burning. Extensive modelling of the geminate rebinding and conformational relaxation kinetics of human hemoglobin show that a satisfactory explanation of a very demanding set of data can be explained by a two- state allosteric model. A laser-photolysis light-scattering technique has been used to monitor intracellular hemoglobin S polymerization in sickle cell disease patients before and after treatment with hydroxyurea. Hydroxyurea therapy leads to a reduction in the fraction of rapidly sickling cells, and an increase in the fraction of non-sickling cells expected from the increase in F cells. The median delay time, however, is still smaller than that observed in SC patients, suggesting that a major therapeutic effect from hydroxyurea should not be expected.

时间分解光谱实验中的光谱法和 分子动力学模拟用于研究蛋白质 血红素蛋白中的折叠和结构功能关系。 快速事件 通过光学触发，正在研究细胞色素C的折叠 与纳秒激光脉冲的折叠反应。 在折叠开始之前 从展开的非本地和天然配体的瞬态结合 已经在微秒的时间范围内观察到多肽。 我们已经证实了我们先前关于 肌红蛋白中构象放松的粘度依赖性 具有“冷冻”分布的肌红蛋白的低温行为 可以在室温玻璃中模仿构象取代物， 包括观察到大量的Geminate重新分布 动力学孔燃烧引起的速率和光谱变化。 Geminate重新构造和构象的广泛建模 人血红蛋白的放松动力学表明令人满意 一组苛刻的数据的解释可以通过两种方式来解释 状态变构模型。 激光 - 光解析光散射技术已用于监测 镰状细胞病患者的细胞内血红蛋白S聚合 羟基脲治疗前后。 羟基脲治疗铅 减少了快速疾病细胞的比例，并增加 在f的增加中，预期的非踢细胞的比例 细胞。 但是，中值延迟时间仍然小于 在SC患者中观察到，这表明来自 不应该期望羟基脲。