BACKGROUND The aggregation of amyloid proteins into fibrils is associated with neurodegenerative diseases such as Alzheimer's and Type II Diabetes. Different methods have explored ways to impede and inhibit amyloid aggregation. Most attempts in the literature involve applying stress to the environment around amyloids. Varying pH levels, modifying temperature, applying pressure through protein crowding and ligand docking are classical examples of these methods. However, environmental stress usually affects molecular pathways and protein functions in the cell and is challenging to construct in vivo. In this paper, we explore destabilizing amyloid proteins through the manipulation of genetic code to create beneficial substitute molecules for patients with certain deficiencies. RESULTS To unravel sequence mutations that destabilize amyloid fibrils yet simultaneously conserve native fold, we analyze the structural landscape of amyloid proteins and search for potential areas that could be exploited to weaken aggregation. Our tool, FibrilMutant, analyzes these regions and studies the effect of amino acid point mutations on nucleation and aggregation. This multiple objective approach impedes aggregation without stressing the cellular environment. We identified six main regions in amyloid proteins that contribute to structural stability and generated amino acid mutations to destabilize those regions. Full length fibrils were built from the mutated amyloid monomers and a dipolar-solvent model capturing the effect of dipole-dipole interactions between water and very large molecular systems to assess their aqueous stability was used to generate energy plots. CONCLUSION Our results are in agreement with experimental studies and suggest novel targeted single point mutations in the Amylin protein, potentially creating a better therapeutic agent than the currently administered Pramlintide drug for diabetes patients.

中文翻译：

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淀粉样蛋白生成潜力降低的淀粉样蛋白序列的计算重组。

背景技术淀粉样蛋白聚集成原纤维与神经退行性疾病如阿尔茨海默氏病和II型糖尿病有关。不同的方法已经探索了阻止和抑制淀粉样蛋白聚集的方法。文献中的大多数尝试都涉及对淀粉样蛋白周围的环境施加压力。这些方法的经典示例包括变化pH值，改变温度，通过蛋白质拥挤和配体对接施加压力。但是，环境压力通常会影响细胞中的分子途径和蛋白质功能，并且难以在体内构建。在本文中，我们通过操纵遗传密码来探索失稳的淀粉样蛋白，从而为患有某些缺陷的患者创造有益的替代分子。结果为了揭示破坏淀粉样蛋白原纤维稳定但同时保留天然折叠的序列突变，我们分析了淀粉样蛋白的结构态势，并寻找可用于削弱聚集的潜在区域。我们的工具FibrilMutant分析了这些区域并研究了氨基酸点突变对成核和聚集的影响。这种多目标方法可在不给细胞环境造成压力的情况下阻止聚集。我们确定了淀粉样蛋白中的六个主要区域，这些区域有助于结构稳定性并产生氨基酸突变来使这些区域不稳定。从突变的淀粉样蛋白单体构建全长原纤维，并使用捕捉水和非常大的分子系统之间偶极-偶极相互作用的影响以评估其水稳定性的偶极溶剂模型来生成能量图。结论我们的结果与实验研究一致，表明胰岛淀粉样多肽蛋白中新的靶向单点突变，与目前用于糖尿病患者的普兰林肽药物相比，可能创造出更好的治疗药物。