Verma Sharad, Singh Amit, Mishra Abha
a School of Biochemical Engineering , Indian Institute of Technology (Banaras Hindu University) , Varanasi 221005 , India.
J Biomol Struct Dyn. 2015;33(5):1094-106. doi: 10.1080/07391102.2014.931823. Epub 2014 Jul 14.
Apoptosis (programmed cell death) is a process by which cells died after completing physiological function or after a severe genetic damage. Apoptosis is mainly regulated by the Bcl-2 family of proteins. Anti apoptotic protein Bcl-2 prevents the Bax activation/oligomerization to form heterodimer which is responsible for release of the cytochrome c from mitochondria to the cytosol in response to death signal. Quercetin and taxifolin (natural polyphenols) efficiently bound to hydrophobic groove of Bcl-2 and altered the structure by inducing conformational changes. Taxifolin was found more efficient when compared to quercetin in terms of interaction energy and collapse of hydrophobic groove. Taxifolin and quercetin were found to dissociate the Bcl-2-Bax complex during 12 ns MD simulation. The effect of taxifolin and quercetin was, further validated by the MD simulation of ligand-unbound Bcl-2-Bax which showed stability during the simulation. Obatoclax (an inhibitor of Bcl-2) had no significant dissociation effect on Bcl-2-Bax during simulation which favored the previous experimental results and disruption effect of taxifolin and quercetin.
细胞凋亡（程序性细胞死亡）是细胞在完成生理功能后或遭受严重基因损伤后死亡的过程。细胞凋亡主要受Bcl-2蛋白家族调控。抗凋亡蛋白Bcl-2可阻止Bax激活/寡聚化形成异二聚体，而异二聚体在死亡信号作用下负责将细胞色素c从线粒体释放到细胞质中。槲皮素和花旗松素（天然多酚）能有效结合到Bcl-2的疏水凹槽，并通过诱导构象变化改变其结构。就相互作用能量和疏水凹槽塌陷而言，花旗松素比槲皮素更有效。在12纳秒的分子动力学模拟中，发现花旗松素和槲皮素能使Bcl-2-Bax复合物解离。未结合配体的Bcl-2-Bax的分子动力学模拟进一步验证了花旗松素和槲皮素的作用，该模拟显示其在模拟过程中具有稳定性。奥巴托拉唑（一种Bcl-2抑制剂）在模拟过程中对Bcl-2-Bax没有显著的解离作用，这支持了先前的实验结果以及花旗松素和槲皮素的破坏作用。
