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

 描述（由申请人提供）：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，并且在脱落之后，至少部分地与它们的内壳沃茨相互作用。因此，机械的见解需要一个精确的知识，如何离子结合的能量/结构/动力学之间的水合和生物分子结合状态的不同。虽然第一原理量子力学模型可以产生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，非极化模型可以在技术上解决采样/系统大小问题，但它们严重影响准确性。极化模型确实提供了一个长期可持续的妥协，但现在有明确的证据表明，这种模型中的误差远远没有达到理想的< 1 kcal/mol的目标。然而，最近的一系列研究提供了令人鼓舞的结果，可用于建立基础工作并显着提高可靠性。虽然所有流行的极化模型的误差都很大，但至少在所研究的案例中，它们是系统性的。此外，至少有两种短程电子效应未包括在可极化模型中，并且其贡献是实质性的并且与可转移性误差相关：（i）离子与其配位配体之间的电荷再分布，其与电荷穿透同义，但是解释了配体作为整体而不是其离子配位官能团的化学变化;（ii）配体C6分散系数的距离依赖性变化。这项研究将基本上测试的假设，即可转移性问题可以通过引入这两个短程电子效应的极化模型，并在不需要重新调整现有的参数的方式来解决。实现这些目标并将这些效应纳入氨基酸、核酸和脂质的极化模型将需要确定它们的具体贡献，这将是 通过一系列第一原理量子力学方法完成，包括CCSD（T），SAPT，DMC和DFT+vdW（目标1）。本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通用方法，将这些影响纳入可极化模型（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。新方法将影响分子力学模型的性质，这些模型适用于除离子以外的广泛化学功能，包括核苷酸、带电脂质和带电氨基酸。能够捕获局部响应特性的模型也将用于增强的采样方法，其中可转移性对于更忠实的表示至关重要。这项工作将产生两个广泛使用的模拟包的新版本和两个极化模型的验证版本，用于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.