Kalmankar Neha V, Gehi Bhuvaneshwari Rajendrakumar, Sowdhamini Ramanathan
National Centre for Biological Sciences (TIFR), GKVK Campus, Bengaluru, Karnataka, India.
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India.
Front Mol Biosci. 2022 Sep 30;9:986704. doi: 10.3389/fmolb.2022.986704. eCollection 2022.
Aggregation of β-amyloid (Aβ) peptide is one of the hallmarks of Alzheimer's disease (AD) which results in chronic and progressive neurodegeneration of the brain. A recent study by our group have shown the ability of cyclic disulfide-rich peptides ("cyclotides") isolated from a medicinal plant, , to inhibit the aggregation of Aβ peptides and reduce oxidative stress caused by reactive oxygen species using models of transgenic . In the present study, through extensive computational docking and multi-ns molecular dynamics (MD) simulation, we evaluated if cyclotides can stably bind to Aβ molecules and/or destabilize the Aβ fibril by preventing conformational changes from α-helical to β-sheet rich structures. We demonstrate that cyclotides bind effectively and stably to different forms of Aβ structures hydrogen bonding and hydrophobic interactions. One of the conserved hydrophobic interface residues, Tyr10 was mutated to Ala and the impact of this virtual mutation was estimated by additional MD simulations for the wild-type (WT) and mutant protein-peptide complexes. A detailed MD simulation analyses revealed that cyclotides form hydrogen bonds with the toxic amyloid assemblies thereby weakening the inter-strand hydrogen bonds between the Aβ peptide. The φ-ѱ distribution map of residues in the cyclotide binding pocket that ideally adopt β-sheet conformation show deviation towards right-handed ɑ-helical (ɑ) conformation. This effect was similar to that observed for the Tyr10Ala mutant and doubly so, for the cyclotide bound form. It is therefore possible to hypothesise that the opening up of amyloid β-sheet is due to an unfolding process occurring in the Aβ caused by cyclotide binding and inhibition. Our current findings provide novel structural insights on the mode of interaction between cyclotides and Aβ fibrils and describe their anti-amyloid aggregation potential. This sheds light on the future of cyclotide-based drug design against protein aggregation, a hallmark event in many neurodegenerative diseases.
β-淀粉样蛋白（Aβ）肽的聚集是阿尔茨海默病（AD）的标志性特征之一，会导致大脑慢性进行性神经退行性变。我们团队最近的一项研究表明，从药用植物中分离出的富含环状二硫键的肽（“环肽”）能够抑制Aβ肽的聚集，并使用转基因模型减少活性氧引起的氧化应激。在本研究中，通过广泛的计算对接和多纳秒分子动力学（MD）模拟，我们评估了环肽是否能通过防止从α-螺旋到富含β-折叠结构的构象变化，稳定地结合到Aβ分子上和/或使Aβ原纤维不稳定。我们证明，环肽通过氢键和疏水相互作用有效地、稳定地结合到不同形式的Aβ结构上。保守的疏水界面残基之一Tyr10突变为Ala，并通过对野生型（WT）和突变体蛋白-肽复合物进行额外的MD模拟来评估这种虚拟突变的影响。详细的MD模拟分析表明，环肽与有毒的淀粉样聚集体形成氢键，从而削弱Aβ肽之间的链间氢键。环肽结合口袋中理想地采用β-折叠构象的残基的φ-ѱ分布图显示向右手α-螺旋（α）构象偏移。这种效应与Tyr10Ala突变体观察到的效应相似，对于环肽结合形式更是如此。因此，可以假设淀粉样β-折叠的打开是由于环肽结合和抑制导致Aβ中发生的解折叠过程。我们目前的研究结果为环肽与Aβ原纤维之间的相互作用模式提供了新的结构见解，并描述了它们的抗淀粉样聚集潜力。这为基于环肽的抗蛋白质聚集药物设计的未来发展提供了线索，蛋白质聚集是许多神经退行性疾病中的标志性事件。
