School of Chemistry, National University of Ireland Galway, Galway H91 TK33, Ireland.
Biointerphases. 2020 Sep 4;15(5):051001. doi: 10.1116/6.0000417.
The formation of dense, linear arrays (fibrils) by biomolecules is the hallmark of a number of degenerative diseases, such as Alzheimer's and type-2 diabetes. Protein fibrils have also attracted interest as building blocks for new materials. It has long been recognized that surfaces can affect the fibrillation process. Recent work on the model fibril forming protein human islet amyloid polypeptide (hIAPP) has shown that while the protein concentration is highest at hydrophobic surfaces, the rate of fibril formation is lower than on other surfaces. To understand this, replica exchange molecular dynamics simulations were used to investigate the conformations that hIAPP adopts on surfaces of different hydrophobicities. The hydrophobic surface stabilizes α-helical structures which are significantly different to those found on the hydrophilic surface and in bulk solution. There is also a greatly reduced conformational ensemble on the hydrophobic surface due to long-lived contacts between hydrophobic residues on the protein and the surface. This new microscopic information will help us determine the mechanism of the enhancement of fibril formation on surfaces and provides new insight into the effect of nanointerfaces and protein conformation.
生物分子形成密集的线性排列（原纤维）是许多退行性疾病的特征，如阿尔茨海默病和 2 型糖尿病。蛋白质原纤维也因其作为新材料构建块而受到关注。长期以来，人们一直认识到表面可以影响纤维化过程。最近对模型原纤维形成蛋白人胰岛淀粉样多肽（hIAPP）的研究表明，虽然蛋白质浓度在疏水面最高，但原纤维形成的速度低于其他表面。为了理解这一点，使用 replica exchange 分子动力学模拟来研究 hIAPP 在不同疏水性表面上采取的构象。疏水面稳定 α-螺旋结构，与亲水面和本体溶液中的结构显著不同。由于蛋白质上的疏水性残基与表面之间存在长时间的接触，疏水面上的构象集合也大大减少。这种新的微观信息将帮助我们确定表面上原纤维形成增强的机制，并为纳米界面和蛋白质构象的影响提供新的见解。
