Probing the configurational space of a metalloprotein core: An ab initio molecular dynamics study of duo ferro 1 binuclear Zn cofactor
Probing the configurational space of a metalloprotein core: An ab initio molecular dynamics study of duo ferro 1 binuclear Zn cofactor
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DOI：
10.1021/ja028161l
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发表时间：
2003-01-15
影响因子：
15
通讯作者：
Klein, ML
中科院分区：
文献类型：
--
作者：
Papoian, GA;DeGrado, WF;Klein, ML
我们提出了三种不同完整程度的理论模型，以探索在从头设计的金属蛋白质Duo Ferro 1的四螺旋束中发现的Glu（4）His（2）Zn（2）辅因子的化学相空间。我们发现，94原子模型I，。其包含蛋白质支架约束以及第二壳氢键网络，以显著的精确度（0.34埃）再现晶体结构键合。令人惊讶的是，66个原子的模型11（缺乏第二壳氢键）和48个原子的模型III（也没有蛋白质支架约束）的几何优化仍然导致与晶体结构的保真度（RMSD分别为0.29和0.34埃）。为了检查这些结构是否接近全局最小值，以及调查各种构象转变的二锌辅因子可能是敏感的，我们已经进行了10 ps的汽车Parrinello分子动力学（CPMD）模拟模型III。我们认为，咪唑氢和羧酸氧之间的弱氢键调节系统的动力学行为。分子的一部分被发现是刚性的，由于特定的H（咪唑）-O（羧酸盐）相互作用限制了咪唑环的运动以及末端羧酸盐的构象迁移率。该系统的后半部分是非常灵活的，展示了耦合的瞬时形成的H（咪唑）-O（羧酸）键与自旋的咪唑环和顺-反异构化的终端羧酸基团。此外，从10 ps CPMD运行的两个低能量快照被淬灭，并优化其几何形状，导致两个新的异构体48 kJ/mol的能量低于与晶体结构相关的。我们建议，周期性淬火的CPMD模拟快照的最低限度的模型可以被用来作为一种有效的方法来产生大量的竞争性的局部极小值，这可能因此修剪通过施加蛋白质支架的约束，以及进一步调整的第二壳氢键网络。
We present three theoretical models of various degree of completeness to explore the chemical phase space available to the Glu(4)His(2)Zn(2) cofactor found in the four-helix bundle of de novo designed metalloprotein Duo Ferro 1. We have found that the planewave DFT geometry optimization of 94-atom Model I,. which contains both the protein scaffold constraints as well as the second shell hydrogen bonding network, reproduces the crystal structure bonding with remarkable accuracy (0.34 Angstrom). Surprisingly, the geometry optimization of 66-atom Model 11 (lacking the second shell hydrogen bonding) and 48-atom Model III (being also free of the protein scaffold constraints) still result in the fidelity with the crystallographic structure (RMSDs 0.29 and 0.34 Angstrom, respectively). To examine whether these structures are close to the global minimum as well as to investigate various conformational transitions to which the di-Zn cofactor may be susceptible to, we have carried out a 10 ps Car-Parrinello Molecular Dynamics (CPMD) simulation of Model Ill. We suggest that weak hydrogen bonds between imidazole hydrogens and carboxylate oxygens modulate the dynamical behavior of the system. One part of the molecule was found to be rigid due to the particular H(imidazole)-O(carboxylate) interaction restricting both the motion of the imidazole ring as well as the terminal carboxylate conformational mobility. The second half of the system was very flexible demonstrating a coupling of a transient formation of H(imidazole)-O(carboxylate) bonds with the spinning of the imidazole ring and syn-anti isomerization of the terminal carboxylate group. In addition, two low-energy snapshots from the 10 ps CPMD run were quenched, and their geometries were optimized, leading to two new isomers 48 kJ/mol lower in energy than the one associated with the crystal structure. We suggest that periodic quenching of the CPMD simulation snapshots of a minimalist model may be used as an efficient method to generate a large number of competitive local minima, which may be consequently pruned by imposing the protein scaffold constraints as well as further tuned by the second shell hydrogen bonding network.