Sethi Aaftaab, Agrawal Nikhil, Brezovsky Jan
Laboratory of Biomolecular Interactions and Transport, Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznanskiego 6, Poznan 61-614, Poland.
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV, Riga 1006, Latvia.
Comput Struct Biotechnol J. 2024 Nov 2;23:3946-3954. doi: 10.1016/j.csbj.2024.10.051. eCollection 2024 Dec.
Protein hydration plays a vital role in many biological functions, and molecular dynamics simulations are frequently used to study it. However, the accuracy of these simulations is often sensitive to the water model used, a phenomenon particularly evident in intrinsically disordered proteins. Here, we investigated the extent to which the choice of water model alters the behavior of complex networks of tunnels within proteins. Tunnels are essential because they allow the exchange of substrates and products between buried enzyme active sites and the bulk solvent, directly affecting enzyme efficiency and selectivity, making the study of tunnels crucial for a holistic understanding of enzyme function at the molecular level. By performing simulations of haloalkane dehalogenase LinB and its two variants with engineered tunnels using TIP3P and OPC models, we investigated their effects on the overall tunnel topology. We also analyzed the properties of the primary tunnels, including their conformation, bottleneck dimensions, sampling efficiency, and the duration of tunnel openings. Our data demonstrate that all three proteins exhibited similar conformational behavior in both models but differed in the geometrical characteristics of their auxiliary tunnels, consistent with experimental observations. Interestingly, the results indicate that the stability of the open tunnels might be sensitive to the water model used. Because TIP3P can provide comparable data on the overall tunnel network, it is a valid choice when computational resources are limited or compatibility issues impede the use of OPC. However, OPC seems preferable for calculations requiring an accurate description of transport kinetics.
蛋白质水合作用在许多生物学功能中起着至关重要的作用，分子动力学模拟经常被用于研究它。然而，这些模拟的准确性往往对所使用的水模型敏感，这种现象在内在无序蛋白质中尤为明显。在这里，我们研究了水模型的选择在多大程度上改变了蛋白质内部复杂隧道网络的行为。隧道至关重要，因为它们允许底物和产物在埋藏的酶活性位点和本体溶剂之间交换，直接影响酶的效率和选择性，使得对隧道的研究对于在分子水平上全面理解酶功能至关重要。通过使用TIP3P和OPC模型对卤代烷脱卤酶LinB及其两个具有工程化隧道的变体进行模拟，我们研究了它们对整体隧道拓扑结构的影响。我们还分析了主要隧道的特性，包括它们的构象、瓶颈尺寸、采样效率以及隧道开口的持续时间。我们的数据表明，在这两种模型中，所有三种蛋白质都表现出相似的构象行为，但它们辅助隧道的几何特征有所不同，这与实验观察结果一致。有趣的是，结果表明开放隧道的稳定性可能对所使用的水模型敏感。由于TIP3P可以提供关于整体隧道网络的可比数据，当计算资源有限或兼容性问题妨碍使用OPC时，它是一个有效的选择。然而，对于需要准确描述传输动力学的计算，OPC似乎更可取。
