Jafari Majid, Sagresti Luca, Hu Jian, Merz Kenneth M
Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan 48824, United States.
Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa, Italy and CSGI.
J Chem Theory Comput. 2025 Apr 22;21(8):4221-4235. doi: 10.1021/acs.jctc.4c01535. Epub 2025 Apr 3.
Metal transporters play crucial roles in the homeostasis and detoxification of beneficial and toxic metals in the human body. Due to experimental limitations in studying some metal transporters, numerous simulation studies have been conducted to understand the mechanisms of metal transport. However, studying the transport of divalent metal ions across the plasma membrane by metal transporters has been challenging with traditional molecular dynamics (MD) simulations. The metal ions often become trapped inside the transporter due to encountering high energy barriers during the transport process. In this study, we combined a recently developed metadynamics setup, known as well-tempered (WT) volume-based MTD, with the 12-6-4 Lennard-Jones (LJ) model representing transition metal-His/Asp/Glu side chain interactions. We used this approach to investigate the mechanism of action of a Zrt-/Irt-like protein (ZIP) transporter and compared the results with simulations using standard 12-6 LJ parameters for the transition metal-His/Asp/Glu side chain interactions. Our results show that the 12-6-4 LJ model for transition metal-His/Asp/Glu side chain interactions samples conformational space more broadly than the standard 12-6 LJ model for the same interactions in MTD simulations, facilitating the sampling of states that are hard to reach with the standard 12-6 model within the same time scale. This is even more remarkable given the fact that the model is dominated by 12-6 LJ interactions for the majority of the system, while the transition metal-His/Asp/Glu side chain interactions are the only interactions using the 12-6-4 LJ model. Hence, a small subset of interactions significantly modifies the states sampled by the entire protein leading to a more frequent observation of the transport of the transition metal ion. Overall, using 12-6-4 LJ to model the transition metal-His/Asp/Glu side chain interactions increases the potential for discovering additional metastable states by enabling metal ions to traverse more freely along the defined transport pathways.
金属转运蛋白在人体中有益和有毒金属的稳态及解毒过程中发挥着关键作用。由于在研究某些金属转运蛋白时存在实验限制，人们进行了大量模拟研究以了解金属转运机制。然而，用传统分子动力学（MD）模拟研究金属转运蛋白介导的二价金属离子跨质膜转运一直具有挑战性。在转运过程中，金属离子常常因遇到高能垒而被困在转运蛋白内部。在本研究中，我们将一种最近开发的元动力学设置（称为温和（WT）体积基元动力学）与代表过渡金属 - 组氨酸/天冬氨酸/谷氨酸侧链相互作用的12 - 6 - 4 Lennard - Jones（LJ）模型相结合。我们用这种方法研究了一种锌铁调控转运蛋白（ZIP）转运体的作用机制，并将结果与使用标准12 - 6 LJ参数模拟过渡金属 - 组氨酸/天冬氨酸/谷氨酸侧链相互作用的结果进行了比较。我们的结果表明，在元动力学模拟中，用于过渡金属 - 组氨酸/天冬氨酸/谷氨酸侧链相互作用的12 - 6 - 4 LJ模型比相同相互作用的标准12 - 6 LJ模型更广泛地采样构象空间，有助于在相同时间尺度内采样标准12 - 6模型难以达到的状态。考虑到该模型在系统的大部分区域由12 - 6 LJ相互作用主导，而过渡金属 - 组氨酸/天冬氨酸/谷氨酸侧链相互作用是唯一使用12 - 6 - 4 LJ模型的相互作用，这一点更为显著。因此，一小部分相互作用显著改变了整个蛋白质采样的状态，导致更频繁地观察到过渡金属离子的转运。总体而言，使用12 - 6 - 4 LJ对过渡金属 - 组氨酸/天冬氨酸/谷氨酸侧链相互作用进行建模，通过使金属离子能够更自由地沿着定义的转运途径穿越，增加了发现额外亚稳态的可能性。
