Rigid-cluster models of conformational transitions in macromolecular machines and assemblies
Rigid-cluster models of conformational transitions in macromolecular machines and assemblies
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DOI：
10.1529/biophysj.104.044347
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发表时间：
2005-07-01
影响因子：
3.4
通讯作者：
Chirikjian, GS
中科院分区：
文献类型：
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作者：
Kim, MK;Jernigan, RL;Chirikjian, GS
我们提出了一种基于刚体的技术(称为刚性簇弹性网络内插)来生成大分子组装的两个不同构象之间的可行过渡路径。许多生物分子和组装体由结构域组成，在大的构象变化中，这些结构域或多或少地充当刚体。这些集体动议被认为与一个系统的功能密切相关。这一事实鼓励我们简单地将一个大分子或组件建模为一组与距离约束相互关联的刚体。在以前的文章中，我们开发了粗粒度弹性网络内插(ENI)，其中，例如，在蛋白质的每个残基中只选择C-α原子作为代表。我们使用一个简单的二次代价函数来对弹性网卡中两个构象的距离差进行内插，从而生成没有空间冲突的可行构象。刚体簇插值法是对弹性网格法的一种扩展，用刚体簇代替点质量。现在，非简谐路径中的中间构象可以由大团簇的平移和转动位移来确定，这种方式是观察到距离约束的。我们给出了刚性团簇模型的推导，并将其应用于各种大分子组装。然后，将刚性簇弹性网卡修改为刚性簇和点质量混合表示的混合模型。仿真结果表明，刚性簇法和混合网格法都能在很短的时间内生成大系统的空间可行路径。例如，HK97病毒衣壳是由60个相同的不对称单位组成的二十面体对称组装。对于C-α粗雨模式，它的原始Hessian矩阵大小是>；(300,000)(2)。然而，当我们应用具有二十面体对称性约束的刚性团簇模型时，它减少到(84)(2)。内插的计算成本不再随着结构的大小而大幅增加；相反，它强烈地依赖于系统可以分解成的最小刚性簇的数量。
We present a rigid-body-based technique (called rigid-cluster elastic network interpolation) to generate feasible transition pathways between two distinct conformations of a macromolecular assembly. Many biological molecules and assemblies consist of domains which act more or less as rigid bodies during large conformational changes. These collective motions are thought to be strongly related with the functions of a system. This fact encourages us to simply model a macromolecule or assembly as a set of rigid bodies which are interconnected with distance constraints. In previous articles, we developed coarse-grained elastic network interpolation (ENI) in which, for example, only C-alpha atoms are selected as representatives in each residue of a protein. We interpolate distance differences of two conformations in ENI by using a simple quadratic cost function, and the feasible conformations are generated without steric conflicts. Rigid-cluster interpolation is an extension of the ENI method with rigid-clusters replacing point masses. Now the intermediate conformations in an anharmonic pathway can be determined by the translational and rotational displacements of large clusters in such a way that distance constraints are observed. We present the derivation of the rigid-cluster model and apply it to a variety of macromolecular assemblies. Rigid-cluster ENI is then modified for a hybrid model represented by a mixture of rigid clusters and point masses. Simulation results show that both rigid-cluster and hybrid ENI methods generate sterically feasible pathways of large systems in a very short time. For example, the HK97 virus capsid is an icosahedral symmetric assembly composed of 60 identical asymmetric units. Its original Hessian matrix size for a C-alpha coarse-rained model is >(300,000)(2). However, it reduces to (84)(2) when we apply the rigid-cluster model with icosahedral symmetry constraints. The computational cost of the interpolation no longer scales heavily with the size of structures; instead, it depends strongly on the minimal number of rigid clusters into which the system can be decomposed.