Accurate and Efficient Modeling of Biomolecular Ionic Interactions: Charge Redistribution, Polarization and Dispersion

 描述(申请人提供)：离子与生物分子的相互作用使许多生理过程成为可能。在大多数情况下，离子直接与生物分子相互作用，并在至少部分脱落后，与生物分子的内壳水相互作用。因此，机械论的洞察需要对离子结合的能量学/结构/动力学在水合状态和生物分子结合状态之间的差异有精确的了解。虽然fiRST原理量子力学模型可以给出相对结合能的可靠估计，但热力学和离子结合响应的估计受到构象采样和系统大小的限制。相比之下，不可极化模型在技术上可以解决采样/系统大小问题，但它们的准确性受到严重影响。可极化模型确实提供了一种长期可持续的折衷方案，但现在有明确的证据表明，此类模型的误差远远达不到理想的1千卡/摩尔目标。然而，最近的一系列研究提供了令人鼓舞的结果，可以用来建立基础工作和显著提高可靠性fi。虽然所有流行的可极化模型的误差都很大，但它们是系统性的，至少对所研究的案例是这样。此外，至少有两种短程电子效应没有被包括在可极化模型中，它们的贡献是实质性的，并与可转移性误差相关：(I)离子与其配位配体之间的电荷重新分配，这是电荷穿透的同义词，但解释了配体作为一个整体的化学变化，而不是其离子配位官能团的变化；(Ii)配体C6色散系数的距离依赖于fi的变化。这项研究将从根本上检验可转移性问题可以通过在可极化模型中引入这两个短程电子效应，并且以不需要重新调整现有参数的方式来解决的假设。要实现这些目标，并将这些效应纳入氨基酸、核酸和脂质的可极化模型中，将需要确定它们的特殊fic贡献，这将是 通过包括fi(T)、SAPT、DMC和DFT+VDW(目标1)在内的CCSD(T)、SAPT(T)、DMC和DFT+VDW(目标1)等一系列量子力学方法来完成。这项研究还将揭示其他电子效应的作用。此外，还需要实施和验证一种将这些效应纳入可极化模型的一般方法(目标2)。系统的量子研究将产生高水平的参考数据，并提高对离子-配体相互作用的理解。新的方法将影响除离子以外的广泛化学功能的分子力学模型的性质，包括核苷酸、带电脂质和带电氨基酸。能够捕获局部响应属性的模型也将被用于增强的抽样方法中，其中可转移性对于更真实的表示是必不可少的。这项工作将产生两个广泛使用的模拟包的新版本和两个可极化模型的验证版本，以有效和准确地模拟生物离子相互作用。

 DESCRIPTION (provided by applicant): Interaction of ions with biomolecules enable many physiological processes. In most cases, ions interact directly with biomolecules and after shedding, at least partially, their inner-shell waters. Consequently, mechanistic insights require a precise knowledge of how the energetics/structures/dynamics of ion-binding differ between hydrated and biomolecule-bound states. While first principles quantum mechanical models can yield reliable estimates for relative binding energies, estimates for thermodynamics and ion-binding response are subject to limitations from conformational sampling and system size. In contrast, non-polarizable models can technically get past sampling/system-size issues, but they suffer severely from accuracy. Polarizable models do offer a long term sustainable compromise, but there is now clear evidence that errors in such models are far from the desired < 1 kcal/mol target. Nevertheless, a series of recent studies provide encouraging results that can be used to build upon the foundational work and enhance reliability significantly. While the errors in all popular polarizable models are large, they are, at least for the cases examined, systematic. Furthermore, there are at least two short-ranged electronic effects that are not included in polarizable models, and whose contributions are substantial and correlated with transferability errors: (i) redistribution of charge between the ion and its coordinating ligands, which is synonymous with charge-penetration, but accounts for variations in the chemistry of the ligand as a whole rather than its ion-coordinating functional group; (ii) distance-dependent variation in ligand C6 dispersion coefficients. This study will essentially tests the hypothesis that the transferability issue can be resolved by introducing these two short-ranged electronic effects in polarizable models, and in a manner that does not require a re-tuning of existing parameters. Achieving these goals and incorporating these effects into polarizable models of amino acids, nucleic acids and lipids will require determination of their specific contributions, which will be accomplished through a hierarchy of first principles quantum mechanical approaches including CCSD(T), SAPT, DMC and DFT+vdW (Aim 1). This study will also reveal the roles of other electronic effects. Additionally, it will require implementation and validation of a general approach to incorporate these effects in polarizable models (Aim 2). The systematic quantum study will generate high-level reference data and improve understanding of ion-ligand interactions. The new approach will impact the nature of molecular mechanics models for a broad spectrum of chemical functionalities other than ions, including nucleotides, charged lipids and charged amino acids. Models capable of capturing local response properties will also find use in enhanced sampling approaches where transferability is essential for a more faithful representation. This work will produce new versions of two widely used simulations packages and validated versions of two polarizable models for efficient and accurate simulations of biological ionic interactions.