Cholesterol Conjugated Elastin-like Recombinamers: Molecular Dynamics Simulations, Conformational Changes, and Bioactivity.

IF 8.2 2区 材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY
ACS Applied Materials & Interfaces Pub Date : 2024-12-04 Epub Date: 2024-11-19 DOI:10.1021/acsami.4c07285
Rui R Costa, Vicente Domínguez-Arca, Brenda Velasco, Rui L Reis, José Carlos Rodríguez-Cabello, Iva Pashkuleva, Pablo Taboada, Gerardo Prieto
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引用次数: 0

Abstract

Current models for elastin-like recombinamer (ELR) design struggle to predict the effects of nonprotein fused materials on polypeptide conformation and temperature-responsive properties. To address this shortage, we investigated the novel functionalization of ELRs with cholesterol (CTA). We employed GROMACS computational molecular dynamic simulations complemented with experimental evidence to validate the in silico predictions. The ELRCTA was biosynthesized and characterized by using fluorescence assays, circular dichroism, dynamic light scattering, and differential scanning calorimetry. The in silico and in vitro data showed that CTA promotes the formation of intramolecular hydrogen bonds that favor β-sheet secondary structures. Compared with an unmodified ELRVKV, CTA enhanced the hydrophobicity and stability of the system, allowing the formation of monodisperse nanoaggregates at physiologically relevant temperatures. Importantly, calorimetry assays revealed that ELRCTA interacted and intercalated with the lipid bilayers of the DPPC liposomes. To demonstrate the implications of these changes for biomedical applications, ELRCTA and DPPC-ELRCTA hybrid nanoparticles were tested with cancer and immune cell lines. Interactions with the cell membranes demonstrated a synergistic effect of the composition and size of the modified recombinamer aggregates on the internalization. The results indicated the potential use of ELR-based nanoparticles for localized and systemic drug delivery. This work sets a new precedent to design elastin-inspired biomaterials with predictable self-assembly properties and develop novel drug delivery strategies.

胆固醇共轭弹性蛋白样重组素:分子动力学模拟、构象变化和生物活性。
目前的弹性蛋白样重组胺(ELR)设计模型难以预测非蛋白融合材料对多肽构象和温度响应特性的影响。为了解决这一不足,我们研究了用胆固醇(CTA)对 ELR 进行功能化的新方法。我们采用了 GROMACS 计算分子动力学模拟,并辅以实验证据来验证硅学预测。我们利用荧光测定法、圆二色法、动态光散射法和差示扫描量热法对 ELRCTA 进行了生物合成和表征。硅学和体外数据显示,CTA 促进了分子内氢键的形成,有利于形成 β 片层二级结构。与未改性的 ELRVKV 相比,CTA 增强了该体系的疏水性和稳定性,使其能够在生理相关温度下形成单分散纳米聚集体。重要的是,量热测定显示,ELRCTA 与 DPPC 脂质体的脂质双分子层发生了相互作用和插层。为了证明这些变化对生物医学应用的影响,我们用癌症和免疫细胞系测试了 ELRCTA 和 DPPC-ELRCTA 混合纳米粒子。与细胞膜的相互作用表明,修饰重组素聚合体的成分和大小对内化有协同作用。研究结果表明,基于 ELR 的纳米颗粒具有局部和全身给药的潜力。这项研究为设计具有可预测自组装特性的弹性蛋白启发生物材料和开发新型给药策略开创了新的先例。
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来源期刊
ACS Applied Materials & Interfaces
ACS Applied Materials & Interfaces 工程技术-材料科学:综合
CiteScore
16.00
自引率
6.30%
发文量
4978
审稿时长
1.8 months
期刊介绍: ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.
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