Khodadadi Ehsaneh, Khodadadi Ehsan, Chaturvedi Parth, Moradi Mahmoud
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA.
Membranes (Basel). 2025 Jun 8;15(6):173. doi: 10.3390/membranes15060173.
Cholesterol plays an essential role in biological membranes and is crucial for maintaining their stability and functionality. In addition to biological membranes, cholesterol is also used in various synthetic lipid-based structures such as liposomes, proteoliposomes, and nanodiscs. Cholesterol regulates membrane properties by influencing the density of lipids, phase separation into liquid-ordered (Lo) and liquid-disordered (Ld) areas, and stability of protein-membrane interactions. For planar bilayers, cholesterol thickens the membrane, decreases permeability, and brings lipids into well-ordered domains, thereby increasing membrane rigidity by condensing lipid packing, while maintaining lateral lipid mobility in disordered regions to preserve overall membrane fluidity. It modulates membrane curvature in curved bilayers and vesicles, and stabilizes low-curvature regions, which are important for structural integrity. In liposomes, cholesterol facilitates drug encapsulation and release by controlling bilayer flexibility and stability. In nanodiscs, cholesterol enhances structural integrity and protein compatibility, which enables the investigation of protein-lipid interactions under physiological conditions. In proteoliposomes, cholesterol regulates the conformational stability of embedded proteins that have implications for protein-lipid interaction. Developments in molecular dynamics (MD) techniques, from coarse-grained to all-atom simulations, have shown how cholesterol modulates lipid tail ordering, membrane curvature, and flip-flop behavior in response to concentration. Such simulations provide insights into the mechanisms underlying membrane-associated diseases, aiding in the design of efficient drug delivery systems. In this review, we combine results from MD simulations to provide a synoptic explanation of cholesterol's complex function in regulating membrane behavior. This synthesis combines fundamental biophysical information with practical membrane engineering, underscoring cholesterol's important role in membrane structure, dynamics, and performance, and paving the way for rational design of stable and functional lipid-based systems to be used in medicine. In this review, we gather evidence from MD simulations to provide an overview of cholesterol's complex function regulating membrane behavior. This synthesis connects the fundamental biophysical science with practical membrane engineering, which highlights cholesterol's important role in membrane structure, dynamics, and function and helps us rationally design stable and functional lipid-based systems for therapeutic purposes.
胆固醇在生物膜中起着至关重要的作用，对于维持其稳定性和功能至关重要。除生物膜外，胆固醇还用于各种基于脂质的合成结构，如脂质体、蛋白脂质体和纳米盘。胆固醇通过影响脂质密度、相分离成液态有序（Lo）和液态无序（Ld）区域以及蛋白质 - 膜相互作用的稳定性来调节膜的性质。对于平面双层膜，胆固醇使膜变厚，降低通透性，并使脂质进入有序区域，从而通过凝聚脂质堆积增加膜的刚性，同时在无序区域保持脂质的横向流动性以维持整体膜流动性。它调节弯曲双层膜和囊泡中的膜曲率，并稳定低曲率区域，这对结构完整性很重要。在脂质体中，胆固醇通过控制双层膜的柔韧性和稳定性促进药物包封和释放。在纳米盘中，胆固醇增强结构完整性和蛋白质兼容性，这使得能够在生理条件下研究蛋白质 - 脂质相互作用。在蛋白脂质体中，胆固醇调节嵌入蛋白质的构象稳定性，这对蛋白质 - 脂质相互作用有影响。分子动力学（MD）技术的发展，从粗粒度模拟到全原子模拟，已经展示了胆固醇如何响应浓度调节脂质尾部排序、膜曲率和翻转行为。此类模拟为膜相关疾病的潜在机制提供了见解，有助于设计高效的药物递送系统。在本综述中，我们结合MD模拟结果，对胆固醇在调节膜行为方面的复杂功能提供一个概要解释。这种综合将基本的生物物理信息与实际的膜工程相结合，强调了胆固醇在膜结构、动力学和性能中的重要作用，并为合理设计用于医学的稳定且功能性的基于脂质的系统铺平了道路。在本综述中，我们收集MD模拟的证据，以概述胆固醇调节膜行为的复杂功能。这种综合将基础生物物理科学与实际膜工程联系起来，突出了胆固醇在膜结构、动力学和功能中的重要作用，并帮助我们合理设计用于治疗目的的稳定且功能性的基于脂质的系统。
