STRUCTURE & DYNAMICS OF CALMODULIN IN SOLUTION: MUSCLE CONTRACTION

结构

• 批准号: 6295247
• 负责人: WILLY R WRIGGERS
• 金额: $ 2.31万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6295247
• 关键词: biomedical resource; computers; enzymes; model design /development; musculoskeletal system; structural biology; technology /technique

To characterize the dynamic behavior of calmodulin in solution, we have carried out molecular dynamics (MD) simulations of the Ca2+-loaded structure* (see reference [91]). The crystal structure of calmodulin was placed in a solvent sphere of radius 44E, and 6 Cl- and 22 Na+ ions were included to neutralize the system and to model a 150 mM salt concentration. The total number of atoms was 32,867. During the 3 ns simulation the structure exhibits large conformational changes on the nanosecond time scale. The central alpha-helix, which has been shown to unwind locally upon binding of calmodulin to target proteins, bends and unwinds near residue Arg74. We interpret this result as a preparative step in the more extensive structural transition observed in the "flexible linker" region 74-82 of the central helix upon complex formation. The major structural change is a reorientation of the two Ca2+-binding domains with respect to each other and a rearrangement of alpha-helices i n the N-terminus domain which make the hydrophobic target peptide binding site more accessible. This structural rearrangement brings the domains to a more favorable position for target binding, poised to achieve the orientation observed in the complex of calmodulin with myosin-light-chain-kinase. Analysis of solvent structure reveals an inhomogeneity in the mobility of water in the vicinity of the protein which is attributable to the hydrophobic effect exerted by calmodulin's binding sites for target peptides.

为了表征溶液中钙调蛋白的动态行为，我们 进行了分子动力学（MD）模拟 Ca2+ 负载结构*（参见参考文献 [91]）。 晶体结构 将钙调蛋白置于半径为 44E、6 Cl- 和 6 Cl- 的溶剂球中 包含 22 个 Na+ 离子来中和系统并模拟 150 mM 盐浓度。 原子总数为32,867。 期间 3 ns 模拟结构表现出大构象 纳秒时间尺度上的变化。 中央α螺旋， 已被证明在钙调蛋白与靶标结合后局部解旋 蛋白质在残基 Arg74 附近弯曲和解旋。 我们解读这个 结果是更广泛的结构性改革的准备步骤 在“柔性接头”区域 74-82 中观察到的转变 复杂形成时的中央螺旋。 主要的结构性变化是 两个 Ca2+ 结合域相对于每个的重新定向 N 末端结构域中的其他和 α 螺旋重排 这使得疏水性目标肽结合位点更多 可以访问。 这种结构上的重新安排使域变得更加 目标绑定处于更有利的位置，准备实现 在钙调蛋白复合物中观察到的方向 肌球蛋白轻链激酶。 溶剂结构分析揭示了 蛋白质附近水的流动性不均匀 这归因于疏水作用 钙调蛋白与目标肽的结合位点。