Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.
Center for Global Health and Infectious Diseases Research, Global and Planetary Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America.
PLoS Comput Biol. 2024 Jul 8;20(7):e1011421. doi: 10.1371/journal.pcbi.1011421. eCollection 2024 Jul.
Membrane binding is a crucial mechanism for many proteins, but understanding the specific interactions between proteins and membranes remains a challenging endeavor. Coagulation factor Va (FVa) is a large protein whose membrane interactions are complicated due to the presence of multiple anchoring domains that individually can bind to lipid membranes. Using molecular dynamics simulations, we investigate the membrane binding of FVa and identify the key mechanisms that govern its interaction with membranes. Our results reveal that FVa can either adopt an upright or a tilted molecular orientation upon membrane binding. We further find that the domain organization of FVa deviates (sometimes significantly) from its crystallographic reference structure, and that the molecular orientation of the protein matches with domain reorganization to align the C2 domain toward its favored membrane-normal orientation. We identify specific amino acid residues that exhibit contact preference with phosphatidylserine lipids over phosphatidylcholine lipids, and we observe that mostly electrostatic effects contribute to this preference. The observed lipid-binding process and characteristics, specific to FVa or common among other membrane proteins, in concert with domain reorganization and molecular tilt, elucidate the complex membrane binding dynamics of FVa and provide important insights into the molecular mechanisms of protein-membrane interactions. An updated version of the HMMM model, termed extHMMM, is successfully employed for efficiently observing membrane bindings of systems containing the whole FVa molecule.
膜结合是许多蛋白质的关键机制，但理解蛋白质与膜之间的特定相互作用仍然是一项具有挑战性的工作。凝血因子 Va（FVa）是一种大型蛋白质，由于存在多个单独可以与脂质膜结合的锚定域，其膜相互作用较为复杂。我们使用分子动力学模拟研究了 FVa 的膜结合，并确定了控制其与膜相互作用的关键机制。我们的结果表明，FVa 在与膜结合时可以采用垂直或倾斜的分子取向。我们进一步发现，FVa 的结构域组织与其晶体学参考结构存在偏离（有时非常明显），并且蛋白质的分子取向与结构域重组相匹配，以使 C2 结构域朝向其优先的膜法向取向对齐。我们确定了特定的氨基酸残基，它们与磷脂酰丝氨酸脂质表现出接触偏好，而不是与磷脂酰胆碱脂质，我们观察到主要是静电效应导致了这种偏好。观察到的脂质结合过程和特征，对于 FVa 或其他膜蛋白共同具有的特征，与结构域重组和分子倾斜一起，阐明了 FVa 的复杂膜结合动力学，并为蛋白质-膜相互作用的分子机制提供了重要的见解。一个名为 extHMMM 的 HMMM 模型的更新版本被成功用于有效地观察包含整个 FVa 分子的系统的膜结合。
