STRUCTURE & DYNAMICS OF CALMODULIN IN SOLUTION: MUSCLE CONTRACTION

为了表征钙调蛋白在溶液中的动态行为，我们 进行了分子动力学(MD)模拟 加钙结构*(见参考文献[91])。该化合物的晶体结构 将钙调蛋白放置在半径为44E和6Cl-的溶剂球体中 包括22个Na+离子，以中和该系统并模拟A150 Mm盐浓度。原子总数为32,867个。在.期间 3 ns模拟结果表明，该结构具有较大的构象 在纳秒时间尺度上的变化。中央的阿尔法螺旋，它 已被证明在钙调蛋白与靶点结合后局部解离 Arg74残基附近的蛋白质、弯曲和解离。我们对此进行了解释 作为更广泛的结构的准备步骤的结果 在“柔性连接子”区域74-82观察到的转变 形成复合体的中心螺旋。主要的结构性变化是 两个钙结合结构域相对于每个结构域的重新定位 N-末端结构域上的其他和α-螺旋的重排 这使得疏水靶肽结合部位更多 无障碍。这种结构的重新安排将域带到了 更有利的位置为目标绑定，准备实现 观察钙调蛋白与钙调素复合体的取向 肌球蛋白轻链激酶。溶剂结构分析揭示了一种 蛋白质附近水的流动性的不均一性 这归因于它所产生的疏水效应 钙调蛋白与靶肽的结合部位。

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.