Fiorin Giacomo, Forrest Lucy R, Faraldo-Gómez José D
National Institute for Neurological Disorders and Stroke, Bethesda, MD, USA.
National Heart, Lung and Blood Institute, Bethesda, MD, USA.
bioRxiv. 2023 Feb 17:2023.02.02.525347. doi: 10.1101/2023.02.02.525347.
All lipid membranes have inherent morphological preferences and resist deformation. Yet adaptations in membrane shape can and do occur at multiple length scales. While this plasticity is crucial for cellular physiology, the factors controlling the morphological energetics of lipid bilayers and the dominant mechanisms of membrane remodeling remain unclear. An ongoing debate regarding the universality of the stiffening effect of cholesterol underscores the challenges facing this field, both experimentally and theoretically, even for simple lipid mixtures. On the computational side, we have argued that enhanced- sampling all-atom molecular dynamics simulations are uniquely suited for quantification of membrane conformational energetics, not only because they minimize a-priori assumptions, but also because they permit analysis of bilayers in deformed states. To showcase this approach, we examine reported inconsistencies between alternative experimental measurements of bending moduli for cholesterol-enriched membranes. Specifically, we analyze lipid bilayers with different chain saturation, and compute free-energy landscapes for curvature deformations distributed over areas from ∼5 to ∼60 nm . These enhanced simulations, totaling over 100 microseconds of sampling time, enable us to directly quantify both bending and tilt moduli, and to dissect the contributing factors and molecular mechanisms of curvature generation at each length scale. Our results show that cholesterol effects are lipid-specific, in agreement with giantvesicle measurements, and explain why experiments probing nanometer scale lipid dynamics diverge. In summary, we demonstrate that quantitative structure-mechanics relationships can now be established for heterogenous membranes, paving the way for addressing open fundamental questions in cell membrane mechanics.
Elucidating the energetics and mechanisms of membrane remodeling is an essential step towards understanding cell physiology. This problem is challenging, however, because membrane bending involves both large-scale and atomic-level dynamics, which are difficult to measure simultaneously. A recent controversy regarding the stiffening effect of cholesterol, which is ubiquitous in animal cells, illustrates this challenge. We show how enhanced molecular-dynamics simulations can bridge this length-scale gap and reconcile seemingly incongruent observations. This approach facilitates a conceptual connection between lipid chemistry and membrane mechanics, thereby providing a solid basis for future research on remodeling phenomena, such as in membrane trafficking or viral infection.
所有脂质膜都有其固有的形态偏好并抵抗变形。然而，膜形状的适应性变化能够且确实发生在多个长度尺度上。虽然这种可塑性对细胞生理学至关重要，但控制脂质双层形态能量学的因素以及膜重塑的主要机制仍不清楚。关于胆固醇硬化效应普遍性的持续争论凸显了该领域在实验和理论方面所面临的挑战，即使对于简单的脂质混合物也是如此。在计算方面，我们认为增强采样的全原子分子动力学模拟特别适合用于量化膜构象能量学，这不仅是因为它们将先验假设减到最少，还因为它们允许对处于变形状态的双层进行分析。为了展示这种方法，我们研究了关于富含胆固醇的膜弯曲模量的不同实验测量之间已报道的不一致性。具体而言，我们分析了具有不同链饱和度的脂质双层，并计算了分布在约5至约60纳米区域内曲率变形的自由能景观。这些增强模拟的采样时间总计超过100微秒，使我们能够直接量化弯曲模量和倾斜模量，并剖析每个长度尺度上曲率产生的影响因素和分子机制。我们的结果表明，胆固醇效应具有脂质特异性，这与巨囊泡测量结果一致，并解释了探测纳米级脂质动力学的实验为何存在分歧。总之，我们证明现在可以为异质膜建立定量的结构 - 力学关系，为解决细胞膜力学中尚未解决的基本问题铺平道路。
阐明膜重塑的能量学和机制是理解细胞生理学的重要一步。然而，这个问题具有挑战性，因为膜弯曲涉及大规模和原子级动力学，而这两者很难同时测量。最近关于动物细胞中普遍存在的胆固醇硬化效应的争议就说明了这一挑战。我们展示了增强分子动力学模拟如何弥合这个长度尺度差距并协调看似不一致的观察结果。这种方法促进了脂质化学与膜力学之间的概念联系，从而为未来关于重塑现象（如膜运输或病毒感染）的研究提供了坚实基础。
