Department of Chemistry, Chicago Center for Theoretical Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, United States.
J Phys Chem B. 2021 Sep 23;125(37):10471-10480. doi: 10.1021/acs.jpcb.1c05992. Epub 2021 Sep 14.
Chemical reactions constitute the central feature of many liquid, material, and biomolecular processes. Conventional molecular dynamics (MD) is inadequate for simulating chemical reactions given the fixed bonding topology of most force fields, while modeling chemical reactions using molecular dynamics is limited to shorter time and length scales given its high computational cost. As such, the multiscale reactive molecular dynamics method provides one promising alternative for simulating complex chemical systems at atomistic detail on a reactive potential energy surface. However, the parametrization of such models is a key barrier to their applicability and success. In this work, we present reactive MD models derived from constrained density functional theory that are both accurate and transferable. We illustrate the features of these models for proton dissociation reactions of amino acids in both aqueous and protein environments. Specifically, we present models for ionizable glutamate and lysine that predict accurate absolute p values in water as well as their significantly shifted p in staphylococcal nuclease (SNase) without any modification of the models. As one outcome of the new methodology, the simulations show that the deprotonation of ionizable residues in SNase can be closely coupled with side chain rotations, which is a concept likely generalizable to many other proteins. Furthermore, the present approach is not limited to only p prediction but can enable the fully atomistic simulation of many other reactive systems along with a determination of the key aspects of the reaction mechanisms.
化学反应是许多液态、物质和生物分子过程的核心特征。鉴于大多数力场的固定键拓扑结构，传统的分子动力学（MD）不足以模拟化学反应，而使用分子动力学模拟化学反应的计算成本很高，因此仅限于较短的时间和长度尺度。因此，多尺度反应分子动力学方法为在反应势能面上模拟复杂化学系统提供了一种很有前途的替代方法，可以实现原子细节的模拟。然而，这种模型的参数化是其适用性和成功的关键障碍。在这项工作中，我们提出了基于约束密度泛函理论的反应性 MD 模型，这些模型既准确又可转移。我们说明了这些模型在模拟氨基酸在水相和蛋白质环境中的质子离解反应中的特点。具体来说，我们提出了可电离谷氨酸和赖氨酸的模型，这些模型可以预测水中准确的绝对 p 值，以及在葡萄球菌核酸酶 (SNase) 中的显著偏移 p 值，而无需对模型进行任何修改。作为新方法的一个结果，模拟表明 SNase 中可电离残基的去质子化可以与侧链旋转紧密耦合，这一概念可能适用于许多其他蛋白质。此外，本方法不仅限于 p 值预测，还可以实现许多其他反应系统的全原子模拟，并确定反应机制的关键方面。
