Development of effective quantum mechanical/molecular mechanical (QM/MM) methods for complex biological processes
Development of effective quantum mechanical/molecular mechanical (QM/MM) methods for complex biological processes
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DOI：
10.1021/jp056361o
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发表时间：
2006-04-06
影响因子：
3.3
通讯作者：
Cui, Q
中科院分区：
文献类型：
--
作者：
Riccardi, D;Schaefer, P;Cui, Q
为了理解生物分子离子泵中质子输运（PT）等载体生物过程的长期目标，建立量子力学/分子力学（QM/MM）联合方法，适用于研究涉及凝聚态中显著电荷分离的化学反应，已经取得了许多进展。对这些发展进行了总结和讨论，并提出了具有代表性的问题。具体而言，采用自由能微扰和边界势方法处理远程静电，以测试蛋白质系统的QM/MM结果的鲁棒性。结果表明，取样充分的一致性模型能够产生定量上令人满意的结果，例如t4溶菌酶内部可滴定基团的pK(a)，而不一致的静电处理或取样不足可能产生不正确的结果。对近似密度泛函理论（SCC-DFTB）进行了修改，以改善质子亲和和氢键的描述，这对极性体系中PT的处理至关重要。水自电离的试验计算清楚地表明，这两种改进对于定量可靠的结果是必要的。最后，采用新建立的SCC-DFTB/MM-GSBP方案探讨碳酸酐酶（CA）的机制问题。初步结果表明，CA中的PT主要通过含有两个水分子的短水线以热活化的方式发生。尽管更长的水线以相似的频率出现，但沿着这些路径的PT平均具有更高的障碍，这是基于先前研究没有预料到的结果。与活性位点的极性蛋白残基相比，水线周围水分子的波动对PT能量学的影响更大，活性位点的极性蛋白残基在很大程度上是预先组织的，因此在反应过程中重组的倾向更小。
Motivated by the long-term goal of understanding vectorial biological processes such as proton transport (PT) in biomolecular ion pumps, a number of developments were made to establish combined quantum mechanical/molecular mechanical (QM/MM) methods suitable for studying chemical reactions involving significant charge separation in the condensed phase. These developments were summarized and discussed with representative problems. Specifically, free energy perturbation and boundary potential methods for treating long-range electrostatics were implemented to test the robustness of QM/MM results for protein systems. It was shown that consistent models with sufficient sampling were able to produce quantitatively satisfactory results, such as pK(a) for titritable groups in the interior of T4-lysozyme, while an inconsistent treatment of electrostatics or lack of sufficient sampling may produce incorrect results. Modifications were made to an approximate density functional theory (SCC-DFTB) to improve the description of proton affinity and hydrogen-bonding, which are crucial for the treatment of PT in polar systems. Test calculations on water autoionization showed clearly that both improvements are necessary for quantitatively reliable results. Finally, the newly established SCC-DFTB/MM-GSBP protocol was used to explore mechanistic issues in carbonic anhydrase (CA). Preliminary results suggest that PT in CA occurs mainly through short water wires containing two water molecules in a thermally activated fashion. Although longer water wires occur with similar frequencies, PT along those pathways, on average, has substantially higher barriers, a result not expected based on previous studies. The fluctuations of water molecules peripheral to the water wire were found to make a larger impact on the PT energetics compared to polar protein residues in the active site, which are largely pre-organized and therefore have less tendency to reorganize during the reaction.