Curtin Medical School, Curtin Health Innovation Research Institute, Curtin Institute for Computation, Curtin University, Perth, Western Australia, Australia.
School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia.
Proteins. 2023 Mar;91(3):338-353. doi: 10.1002/prot.26432. Epub 2022 Oct 7.
Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein (IDP) whose abnormal aggregation into toxic soluble oligomers and insoluble amyloid fibrils is a pathological feature in type-2 diabetes. Rat IAPP (rIAPP) differs from hIAPP by only six amino acids yet has a reduced tendency to aggregate or form fibrils. The structures of the monomeric forms of IAPP are difficult to characterize due to their intrinsically disordered nature. Molecular dynamics simulations can provide a detailed characterization of the monomeric forms of rIAPP and hIAPP in near-physiological conditions. In this work, the conformational landscapes of rIAPP and hIAPP as a function of secondary structure content were predicted using well-tempered bias exchange metadynamics simulations. Several combinations of commonly used biomolecular force fields and water models were tested. The predicted conformational preferences of both rIAPP and hIAPP are typical of IDPs, exhibiting dominant random coil structures but showing a low propensity for transient α-helical conformations. Predicted nuclear magnetic resonance Cα chemical shifts reveal different preferences with each force field towards certain conformations, with AMBERff99SBnmr2/TIP4Pd showing the best agreement with the experiment. Comparisons of secondary structure content demonstrate residue-specific differences between hIAPP and rIAPP that may reflect their different aggregation propensities.
人胰岛淀粉样多肽 (hIAPP) 是一种天然存在的、无规卷曲的蛋白质 (IDP)，其异常聚集形成毒性可溶性寡聚物和不溶性淀粉样纤维是 2 型糖尿病的病理特征。大鼠胰岛淀粉样多肽 (rIAPP) 与 hIAPP 仅相差六个氨基酸，但聚集或形成纤维的趋势降低。由于其无规卷曲的性质，IAPP 单体形式的结构难以表征。分子动力学模拟可以在近生理条件下对 rIAPP 和 hIAPP 的单体形式进行详细表征。在这项工作中，使用经过良好调整的偏置交换元动力学模拟预测了 rIAPP 和 hIAPP 作为二级结构含量函数的构象景观。测试了几种常用的生物分子力场和水模型的组合。预测 rIAPP 和 hIAPP 的构象偏好均为 IDP 的典型特征，表现出主导的无规卷曲结构，但表现出低倾向形成瞬态 α-螺旋构象。预测的核磁共振 Cα化学位移揭示了每个力场对某些构象的不同偏好，其中 AMBERff99SBnmr2/TIP4Pd 与实验吻合度最好。二级结构含量的比较表明 hIAPP 和 rIAPP 之间存在残基特异性差异，这可能反映了它们不同的聚集倾向。
