Jaklin Matej, Brudar Sandi, Hribar-Lee Barbara
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot, 113, SI-1000 Ljubljana, Slovenia.
Z Phys Chem (N F). 2024 Nov 11. doi: 10.1515/zpch-2024-0761.
Amyloids are protein aggregates involved in various protein condensation diseases. Our study aims to investigate the influence of glycine on the fibrillization mechanism of -lactoglobulin (BLG), a model protein known to form amyloid fibrils from hydrolysed peptides in low pH aqueous solutions. We conducted atomistic molecular dynamics simulations of aqueous solutions of native and unfolded BLG in glycine buffer at pH 2.0. During the simulations we put our focus on analysing protein-protein/buffer interactions, structural electrostatic potential mapping, and the residence times of glycine and glycinium near specific amino acid residues. Glycinium cations were found to preferentially interact with specific protein residues potentially masking the outer disulfide bonds, affecting thiol deprotonation and influencing disulfide scrambling equilibrium. These interactions can potentially hinder hydrolysis and change the fibrillization pathway. Further investigations, such as constant pH MD simulations, simulations on disulfide bounded oligomers are warranted to validate these findings and deepen our understanding of protein aggregation mechanisms.
淀粉样蛋白是参与各种蛋白质凝聚疾病的蛋白质聚集体。我们的研究旨在探究甘氨酸对β-乳球蛋白（BLG）纤维化机制的影响，BLG是一种在低pH水溶液中已知可从水解肽形成淀粉样纤维的模型蛋白。我们在pH 2.0的甘氨酸缓冲液中对天然和未折叠的BLG水溶液进行了原子分子动力学模拟。在模拟过程中，我们重点分析了蛋白质-蛋白质/缓冲液相互作用、结构静电势图谱以及甘氨酸和甘氨酸离子在特定氨基酸残基附近的停留时间。发现甘氨酸离子优先与特定的蛋白质残基相互作用，可能掩盖外部二硫键，影响硫醇去质子化并影响二硫键重排平衡。这些相互作用可能会阻碍水解并改变纤维化途径。有必要进行进一步的研究，例如恒定pH分子动力学模拟、对二硫键结合的寡聚体的模拟，以验证这些发现并加深我们对蛋白质聚集机制的理解。
