Borges-Araújo Luís, Souza Paulo C T, Fernandes Fábio, Melo Manuel N
iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon 1049-001, Portugal.
Associate Laboratory i4HB─Institute for Health and Bioeconomy, at Instituto Superior Técnico, Universidade de Lisboa, Lisbon 1049-001, Portugal.
J Chem Theory Comput. 2022 Jan 11;18(1):357-373. doi: 10.1021/acs.jctc.1c00615. Epub 2021 Dec 28.
Phosphoinositides are a family of membrane phospholipids that play crucial roles in membrane regulatory events. As such, these lipids are often a key part of molecular dynamics simulation studies of biological membranes, in particular of those employing coarse-grain models because of the potential long times and sizes of the involved membrane processes. Version 3 of the widely used Martini coarse-grain force field has been recently published, greatly refining many aspects of biomolecular interactions. In order to properly use it for lipid membrane simulations with phosphoinositides, we put forth the Martini 3-specific parameterization of inositol, phosphatidylinositol, and seven physiologically relevant phosphorylated derivatives of phosphatidylinositol. Compared to parameterizations for earlier Martini versions, focus was put on a more accurate reproduction of the behavior seen in both atomistic simulations and experimental studies, including the signaling-relevant phosphoinositide interaction with divalent cations. The models that we develop improve upon the conformational dynamics of phosphoinositides in the Martini force field and provide stable topologies at typical Martini time steps. They are able to reproduce experimentally known protein-binding poses as well as phosphoinositide aggregation tendencies. The latter was tested both in the presence and absence of calcium and included correct behavior of PI(4,5)P calcium-induced clusters, which can be of relevance for regulation.
磷酸肌醇是一类膜磷脂，在膜调节事件中发挥着关键作用。因此，这些脂质通常是生物膜分子动力学模拟研究的关键部分，特别是对于那些采用粗粒度模型的研究，因为所涉及的膜过程可能具有较长的时间和较大的规模。广泛使用的Martini粗粒度力场的第3版最近已发布，极大地改进了生物分子相互作用的许多方面。为了将其正确用于含磷酸肌醇的脂质膜模拟，我们提出了针对肌醇、磷脂酰肌醇以及七种生理相关的磷脂酰肌醇磷酸化衍生物的Martini 3特定参数化。与早期Martini版本的参数化相比，重点在于更准确地再现原子模拟和实验研究中观察到的行为，包括与二价阳离子的信号相关磷酸肌醇相互作用。我们开发的模型改进了Martini力场中磷酸肌醇的构象动力学，并在典型的Martini时间步长下提供了稳定的拓扑结构。它们能够再现实验已知的蛋白质结合姿势以及磷酸肌醇聚集趋势。后者在有钙和无钙的情况下都进行了测试，包括PI(4,5)P钙诱导簇的正确行为，这可能与调节有关。
