Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal By-pass Road, Bhauri, Bhopal, 462066, MP, India.
Mol Inform. 2018 May;37(5):e1700105. doi: 10.1002/minf.201700105. Epub 2017 Oct 12.
GTP hydrolysis is indispensable to keep a living cell healthy. Nature has evolved so many enzymes to enhance the slow GTP hydrolysis. Rab GTPases are evolved to regulate vesicle trafficking. GTPase activating proteins (GAPs) accelerates their intrinsic slow GTP hydrolysis in order to maintain the sustainability between cellular events. Any malfunction/interference in this hydrolysis disrupts normal cellular events and causes severe diseases. In this study, GTP hydrolysis mechanism of Rab33B catalyzed by TBC-domain GAP protein Gyp1p has been decoded using extensive ab initio QM/MM metadynamics simulations. An organized coupled movement of individual residues present at the catalytic site is found to be the key factor for this reaction. An unorganized coupled movement leads the hydrolysis through very high energy pathways. This also reveals that the chemical transformations occurring at a catalytic site are residue specific.
GTP 水解对于保持活细胞的健康是不可或缺的。自然界已经进化出许多酶来增强 GTP 的缓慢水解。Rab GTPases 进化来调节囊泡运输。GTP 酶激活蛋白 (GAP) 加速它们内在的缓慢 GTP 水解，以维持细胞事件之间的可持续性。这种水解的任何功能障碍/干扰都会破坏正常的细胞事件，并导致严重的疾病。在这项研究中，使用广泛的从头 QM/MM 元动力学模拟，解码了 Rab33B 由 TBC 结构域 GAP 蛋白 Gyp1p 催化的 GTP 水解机制。发现在催化部位存在的单个残基的有组织的偶联运动是该反应的关键因素。无组织的偶联运动使水解通过非常高的能量途径进行。这也表明发生在催化部位的化学转化是残基特异性的。
