Jepsen Lauren, Sept David
Department of Biomedical Engineering and Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
Department of Biomedical Engineering and Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
Biophys J. 2020 Nov 3;119(9):1800-1810. doi: 10.1016/j.bpj.2020.09.024. Epub 2020 Sep 28.
The regulation of actin is key for controlled cellular function. Filaments are regulated by actin-binding proteins, but the nucleotide state of actin is also an important factor. From extended molecular dynamics simulations, we find that both nucleotide states of the actin monomer have significantly less twist than their crystal structures and that the ATP monomer is flatter than the ADP form. We also find that the filament's pointed end is flatter than the remainder of the filament and has a conformation distinct from G-actin, meaning that incoming monomers would need to undergo isomerization that would weaken the affinity and slow polymerization. Conversely, the barbed end of the filament takes on a conformation nearly identical to the ATP monomer, enhancing ATP G-actin's ability to polymerize as compared with ADP G-actin. The thermodynamic penalty imposed by differences in isomerization for the ATP and ADP growth at the barbed end exactly matches experimental results.
肌动蛋白的调节是细胞功能可控的关键。肌动蛋白丝由肌动蛋白结合蛋白调节，但肌动蛋白的核苷酸状态也是一个重要因素。通过扩展分子动力学模拟，我们发现肌动蛋白单体的两种核苷酸状态的扭曲程度都明显低于其晶体结构，且ATP单体比ADP形式更扁平。我们还发现，肌动蛋白丝的尖端比丝的其余部分更扁平，并且具有与G-肌动蛋白不同的构象，这意味着进入的单体需要进行异构化，这会削弱亲和力并减缓聚合反应。相反，肌动蛋白丝的另一端的构象与ATP单体几乎相同，与ADP G-肌动蛋白相比，增强了ATP G-肌动蛋白的聚合能力。在另一端，ATP和ADP生长的异构化差异所带来的热力学惩罚与实验结果完全匹配。
