基于弹性网络的锌指蛋白局域分子场分析
An elastic-network based local molecular field analysis of zinc-finger proteins
摘要：
我们研究了两个设计的和一个天然的锌指肽，每个与Cys 2 His 2（CCHH）型的金属结合基序。在我们已经开发的方法中，我们描述的Zn（II）-CCHH金属残基簇外的蛋白质和溶剂的作用由广义谐波约束所代表的分子场。调整电场强度，以再现金属与经验势的参考全原子模拟中获得的簇的结合能分布。二次场使我们能够分析研究结合位点上的蛋白质限制在其本征模。检查这些本征模表明，与实验观察一致，CCHH簇中第一个组氨酸（H）在金属结合中的重要性。此外，对应于这些模式的本征值也表明，所设计的蛋白质与金属形成更紧密的复合物。我们发现，大量的蛋白质和溶剂的反应往往不稳定的金属结合，强调有利的能量的金属残基相互作用是必要的，以驱动折叠在这个系统中。的散装蛋白质和溶剂的本地字段的响应的表示允许我们使用量子化学方法，这里使用半经验的哈密顿量的金属残基集群进行蒙特卡罗模拟。对于从该模拟中取样的构型，我们使用密度泛函理论研究了用Fe（II）、Co（II）和Ni（II）取代Zn（II）的自由能。计算的选择性是在公平的协议与实验结果。
英文摘要：
We study two designed and one natural zinc-finger peptide each with the Cys2His2 (CCHH) type of metal binding motif. In the approach we have developed, we describe the role of the protein and solvent outside the Zn(II)-CCHH metal-residue cluster by a molecular field represented by generalized harmonic restraints. The strength of the field is adjusted to reproduce the binding energy distribution of the metal with the cluster obtained in a reference all-atom simulation with empirical potentials. The quadratic field allows us to investigate analytically the protein restraints on the binding site in terms of its eigenmodes. Examining these eigenmodes suggests, consistent with experimental observations, the importance of the first histidine (H) in the CCHH cluster in metal binding. Further, the eigenvalues corresponding to these modes also indicate that the designed proteins form a tighter complex with the metal. We find that the bulk protein and solvent response tends to destabilize metal-binding, emphasizing that the favorable energetics of metal-residue interaction is necessary to drive folding in this system. The representation of the bulk protein and solvent response by a local field allows us to perform Monte Carlo simulations of the metal-residue cluster using quantum-chemical approaches, here using a semi-empirical Hamiltonian. For configurations sampled from this simulation, we study the free energy of replacing Zn(II) with Fe(II), Co(II), and Ni(II) using density functional theory. The calculated selectivities are in fair agreement with experimental results.
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