Representation of Ion-Protein Interactions Using the Drude Polarizable Force-Field.
Representation of Ion-Protein Interactions Using the Drude Polarizable Force-Field.
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DOI：
10.1021/jp510560k
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发表时间：
2015-07-23
期刊：
影响因子：
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通讯作者：
Noskov SY
中科院分区：
文献类型：
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作者：
Li H;Ngo V;Da Silva MC;Salahub DR;Callahan K;Roux B;Noskov SY
小金属离子在众多生物过程中起着关键作用。特别令人感兴趣的是金属酶如何通过特定离子的结合进行变构调节。要理解离子结合如何影响这些生物过程，就需要能够准确处理与蛋白质配体微观相互作用的原子模型。不同复杂程度的理论方法有助于更深入地理解这些系统，不过计算模型必须在准确性和效率之间取得平衡，以便能够进行长时间的分子动力学模拟。在这项研究中，我们进行了一项系统性的工作，基于经典的德鲁德振子优化可极化力场的参数，以便准确表示离子（K⁺、Na⁺、Ca²⁺和Cl⁻）与一组30种具有重要生物学意义的蛋白质的配位氨基酸残基之间的相互作用。通过结合从头算计算和实验热力学数据，我们推导出一种可极化力场，它与多种性质相符，包括气相离子/类蛋白质模型化合物簇的几何结构和相互作用能，以及阳离子在液体中的实验溶剂化自由能。所得模型相对于固定原子电荷加和性CHARMM C36力场有显著改进，特别是在重现从头算计算所估计的多体静电非加和性效应的能力方面。该分析阐明了经典固定电荷力场固有的成对加和性假设的基本局限性，并显示了它在Ca²⁺结合位点情况下的严重失败。这些经过优化的可极化模型适用于计算高效的大规模分子动力学模拟，为研究离子在可溶性和膜转运蛋白中的作用奠定了坚实基础，并提供了一条有力途径。
Small metal ions play critical roles in numerous biological processes. Of particular interest is how metalloenzymes are allosterically regulated by the binding of specific ions. Understanding how ion binding affects these biological processes requires atomic models that accurately treat the microscopic interactions with the protein ligands. Theoretical approaches at different levels of sophistication can contribute to a deeper understanding of these systems, although computational models must strike a balance between accuracy and efficiency in order to enable long molecular dynamics simulations. In this study, we present a systematic effort to optimize the parameters of a polarizable force field based on classical Drude oscillators to accurately represent the interactions between ions (K+, Na+, Ca2+, and Cl–) and coordinating amino-acid residues for a set of 30 biologically important proteins. By combining ab initio calculations and experimental thermodynamic data, we derive a polarizable force field that is consistent with a wide range of properties, including the geometries and interaction energies of gas-phase ion/protein-like model compound clusters, and the experimental solvation free-energies of the cations in liquids. The resulting models display significant improvements relative to the fixed-atomic-charge additive CHARMM C36 force field, particularly in their ability to reproduce the many-body electrostatic nonadditivity effects estimated from ab initio calculations. The analysis clarifies the fundamental limitations of the pairwise additivity assumption inherent in classical fixed-charge force fields, and shows its dramatic failures in the case of Ca2+ binding sites. These optimized polarizable models, amenable to computationally efficient large-scale MD simulations, set a firm foundation and offer a powerful avenue to study the roles of the ions in soluble and membrane transport proteins.