生物大分子NMR光谱的量子化学计算以及金属蛋白力场的开发和应用
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摘要
近年来,随着理论方法不断的发展以及计算机能力的持续提高,量子化学(Quantum Chemistry)计算越来越多的成为研究生物大分子结构和功能的重要手段。然而,由于量化计算在处理大体系时需要极高的计算量,它只能处理生物体系内的一部分,直至今日也无法直接应用到生物大分子的研究,因此人们不得不致力于发展各种近似方法以拓宽其应用。本论文的工作主要集中于2个方面的研究：(1),进一步发展了针对生物大分子的NMR化学位移进行全量化计算的AF-QM/MM (Automated Fragmentation Quantum Mechanics/Molecular Mechanics)方法在溶液中的应用；(2),发展了基于量子化学计算的包含电荷转移及静电极化效应的分子力场QPCT (Non-bonded quantum-calibrated polarizable-charge transfer force field)>用来准确描述含锌蛋白的结构和动力学性质。
在AF-QM/MM方法中,我们把蛋白质分子在肽键位置切开,得到若干个氨基酸片段,作为核心(core)区域,将核心区域附近一定距离内,对核心区域原子的化学位移有影响的化学基团,如氢键供体/受体,芳香环,带电基团等,选为缓冲区(buffer),核心区和缓冲区的原子采用量子化学计算,体系内其他原子对核心区的影响用分子力学(Molecular mechanics, MM)来模拟,最后将每个核心区域上原子的化学位移收集起来就得到了整个蛋白的化学位移。在此基础上我们将AF-QM/MM方法和泊松-波尔兹曼溶剂化模型(PB Model)以及显式溶剂模型结合起来,实现了非均匀介质中和溶液中的蛋白质化学位移的全量子化学计算。采用AF-QM/MM方法我们可以把含有N个残基的蛋白划分为N个片段来分别处理,从而实现了线性标度,大大提高了计算效率。大量的测试和研究表明,采用该方法后我们可以精确地计算蛋白质中所有主要原子的化学位移,并且可以将其应用到蛋白的结构预测以及优化中。AF-QM/MM方法首次系统的将从头算或DFT方法引入到化学位移的计算中来,不依赖于现有经验数据,适用性更广,可信度也更高。该方法还适用于非蛋白体系,如DNA,RNA等,这是目前的经验程序无法胜任的工作。
大量的理论研究已经证明,采用现有的经典力场来研究金属蛋白的动力学性质是极其不可靠的。尽管人们都认为这是因为力场中缺乏极化和电荷转移等量化效应,但是鲜有更加精确的力场参数被提出来。在本文的工作中,我们提出了一种处理含锌离子蛋白的新的分子力场：QPCT。在该方法中,蛋白中所有极性较强的化学键的极化态都可以根据整个蛋白以及溶剂的静电环境来调整,因此整个体系的长程静电相互作用可以很好的被处理。此外,锌离子和它的配体之间的相互作用采用了量化计算进行校正,电荷转移效应也被考虑了进来。该方法在多个含锌体系以及锌离子的多种配位模式下都进行了测试,计算结果清晰的表明考虑极化和电荷转移效应后,QPCT可以在模拟过程中正确的稳定锌离子配位区域的结构,并可以用来研究含锌蛋白的结构优化以及计算金属蛋白和配体的相互作用。QPCT方法在考虑量子效应的同时,其函数形式跟现有力场高度相关,因此非常容易参数化,计算效率也可以得到保证,实际的测试表明,采用该力场对含锌蛋白进行分子动力学模拟只比传统力场多消耗不过1%的计算时间。
Recently, in the wake of developments in theory and computer science, quantum chemistry calculation is more and more used to explore the structure and function of bio-molecules. However, the quantum calculation needs massively computer resources, thus cannot be applied on large systems like proteins directly. Therefore, people have to develop variously approximation methods to expand its application limits. The main work of this study completed as follows:first, we introduced the solvent effect into the AF-QM/MM (Automated Fragmentation Quantum Mechanics/Molecular Mechanics) model based on Divide&Conquer theory, which can calculate the protein chemical shifts using quantum chemistry method, and then, we proposed a new force field for study of zinc protein:QPCT (Non-bonded quantum-calibrated polarizable-charge transfer force field).
In the AF-QM/MM approach, the entire protein is divided into non-overlapping fragments termed core regions. The residues within a certain range from the core region are included in the buffer region. Both the core and the buffer regions are treated by quantum mechanics, while the remainder of the protein is described using an empirical point-charge model to account for the electrostatic effect. Each core-centric (core+buffer) QM/MM calculation is carried out separately and only the chemical shifts of the atoms in the core region are extracted from individual QM/MM calculation. By using PB model and explicit waters, the solvation effects are also included in AF-QM/MM method. Using this scheme, we can divide the entire protein into undependable fragments, thus the calculation is totally linear-scaling. Our calculated chemical shifts of1H and13C and15N atoms of proteins are in remarkable agreement with experimentally measured values and also can be used to predict and refine protein structures. The applications may also be extended to more general biological systems, such as nonstandard residues, metalloproteins, protein-ligand, protein-DNA/RNA and membrane protein-lipid complexes.
Although making great improvement over the past two decades, most today's force fields do not always have appropriate parameters for metal atoms, which has become a practical obstacle for the molecular modeling studies of metalloproteins. In the current work, the QPCT force field was proposed to capture the polarization and charge transfer contributions to the interatomic interactions for zinc-proteins. These parameters were validated extensively in molecular dynamic simulations of hydration shell of zinc ion and five proteins containing most common zinc-binding sites as well as one protein-ligand complex. The calculated results of QPCT show excellent agreement with the experimental measurements and QM/MM MD simulations, demonstrating that the present approach can provide enough accuracy to maintain the integrity of the zinc binding pocket during extended molecular dynamic simulations. The QPCT method is easily to parameterize and transfer to other systems having the same coordinate geometry, and it can also be extended to study the interaction of other metals that have large charge transfer and polarization effects.
在AF-QM/MM方法中,我们把蛋白质分子在肽键位置切开,得到若干个氨基酸片段,作为核心(core)区域,将核心区域附近一定距离内,对核心区域原子的化学位移有影响的化学基团,如氢键供体/受体,芳香环,带电基团等,选为缓冲区(buffer),核心区和缓冲区的原子采用量子化学计算,体系内其他原子对核心区的影响用分子力学(Molecular mechanics, MM)来模拟,最后将每个核心区域上原子的化学位移收集起来就得到了整个蛋白的化学位移。在此基础上我们将AF-QM/MM方法和泊松-波尔兹曼溶剂化模型(PB Model)以及显式溶剂模型结合起来,实现了非均匀介质中和溶液中的蛋白质化学位移的全量子化学计算。采用AF-QM/MM方法我们可以把含有N个残基的蛋白划分为N个片段来分别处理,从而实现了线性标度,大大提高了计算效率。大量的测试和研究表明,采用该方法后我们可以精确地计算蛋白质中所有主要原子的化学位移,并且可以将其应用到蛋白的结构预测以及优化中。AF-QM/MM方法首次系统的将从头算或DFT方法引入到化学位移的计算中来,不依赖于现有经验数据,适用性更广,可信度也更高。该方法还适用于非蛋白体系,如DNA,RNA等,这是目前的经验程序无法胜任的工作。
大量的理论研究已经证明,采用现有的经典力场来研究金属蛋白的动力学性质是极其不可靠的。尽管人们都认为这是因为力场中缺乏极化和电荷转移等量化效应,但是鲜有更加精确的力场参数被提出来。在本文的工作中,我们提出了一种处理含锌离子蛋白的新的分子力场：QPCT。在该方法中,蛋白中所有极性较强的化学键的极化态都可以根据整个蛋白以及溶剂的静电环境来调整,因此整个体系的长程静电相互作用可以很好的被处理。此外,锌离子和它的配体之间的相互作用采用了量化计算进行校正,电荷转移效应也被考虑了进来。该方法在多个含锌体系以及锌离子的多种配位模式下都进行了测试,计算结果清晰的表明考虑极化和电荷转移效应后,QPCT可以在模拟过程中正确的稳定锌离子配位区域的结构,并可以用来研究含锌蛋白的结构优化以及计算金属蛋白和配体的相互作用。QPCT方法在考虑量子效应的同时,其函数形式跟现有力场高度相关,因此非常容易参数化,计算效率也可以得到保证,实际的测试表明,采用该力场对含锌蛋白进行分子动力学模拟只比传统力场多消耗不过1%的计算时间。
Recently, in the wake of developments in theory and computer science, quantum chemistry calculation is more and more used to explore the structure and function of bio-molecules. However, the quantum calculation needs massively computer resources, thus cannot be applied on large systems like proteins directly. Therefore, people have to develop variously approximation methods to expand its application limits. The main work of this study completed as follows:first, we introduced the solvent effect into the AF-QM/MM (Automated Fragmentation Quantum Mechanics/Molecular Mechanics) model based on Divide&Conquer theory, which can calculate the protein chemical shifts using quantum chemistry method, and then, we proposed a new force field for study of zinc protein:QPCT (Non-bonded quantum-calibrated polarizable-charge transfer force field).
In the AF-QM/MM approach, the entire protein is divided into non-overlapping fragments termed core regions. The residues within a certain range from the core region are included in the buffer region. Both the core and the buffer regions are treated by quantum mechanics, while the remainder of the protein is described using an empirical point-charge model to account for the electrostatic effect. Each core-centric (core+buffer) QM/MM calculation is carried out separately and only the chemical shifts of the atoms in the core region are extracted from individual QM/MM calculation. By using PB model and explicit waters, the solvation effects are also included in AF-QM/MM method. Using this scheme, we can divide the entire protein into undependable fragments, thus the calculation is totally linear-scaling. Our calculated chemical shifts of1H and13C and15N atoms of proteins are in remarkable agreement with experimentally measured values and also can be used to predict and refine protein structures. The applications may also be extended to more general biological systems, such as nonstandard residues, metalloproteins, protein-ligand, protein-DNA/RNA and membrane protein-lipid complexes.
Although making great improvement over the past two decades, most today's force fields do not always have appropriate parameters for metal atoms, which has become a practical obstacle for the molecular modeling studies of metalloproteins. In the current work, the QPCT force field was proposed to capture the polarization and charge transfer contributions to the interatomic interactions for zinc-proteins. These parameters were validated extensively in molecular dynamic simulations of hydration shell of zinc ion and five proteins containing most common zinc-binding sites as well as one protein-ligand complex. The calculated results of QPCT show excellent agreement with the experimental measurements and QM/MM MD simulations, demonstrating that the present approach can provide enough accuracy to maintain the integrity of the zinc binding pocket during extended molecular dynamic simulations. The QPCT method is easily to parameterize and transfer to other systems having the same coordinate geometry, and it can also be extended to study the interaction of other metals that have large charge transfer and polarization effects.
引文
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