Muneeswaran Gurusamy, Kartheeswaran Subramanian, Muthukumar Kaliappan, Dharmaraj Christopher D, Karunakaran Chandran
Biomedical Research Lab, Department of Chemistry, VHNSN College (Autonomous), Virudhunagar, 626 001, Tamilnadu, India.
Department of Computer Applications, School of Computing, Kalasalingam University, Krishnanakoil, 626 126, Tamil Nadu, India.
J Mol Graph Model. 2017 Sep;76:234-241. doi: 10.1016/j.jmgm.2017.06.020. Epub 2017 Jul 14.
Cytochrome c (cyt-c) upon binding with cardiolipin acquires peroxidase activity and is strictly connected to the pathogenesis of many human diseases including neurodegenerative and cardiovascular diseases. Interaction of cyt-c with cardiolipin mimics partial unfolding/conformational changes of cyt-c in different solvent environments. Dynamic pictures of these conformational changes of cyt-c are crucial in understanding their physiological roles in mitochondrial functions. Therefore, atomistic molecular dynamics (MD) simulations have been carried out to investigate the effect of different solvents (water, urea/water, MeOH and DMSO) on the structure and conformations of apoptotic cyt-c (Fe). Our study demonstrates that the structural changes in the protein are solvent dependent. The structural differences are observed majorly on the β-sheets and α-helical conformations and the degree of their perturbation are specific to the solvent. Although a complete loss of β-sheets (0%) is observed in MeOH and DMSO, by contrast, well preserved β-sheets (3.84%) are observed in water and urea/water. A significant decrease in the α-helical contents is observed in MeOH (41.34%) and water (42.46%), a negligible alteration in DMSO (44.25%) and well preserved α-helical (45.19%) contents in urea/water. The distances between the residues critical for electron transfer are decreased considerably for DMSO. Further, the reduction in residue flexibility and the conformational space indicate that the collective motions of cyt-c are reduced when compared to other cosolvents. Essential dynamics analysis implies that the overall motions of cyt-c in water, MeOH and urea/water are involved in three to four eigenvectors and in first eigenvector in DMSO. Overall, we believe that MD simulations of cyt-c in different solvents can provide a detailed microscopic understanding of the physiological roles, electron transport and peroxidase function in the early events of apoptosis which are hard to probe experiments.
细胞色素c（cyt-c）与心磷脂结合后获得过氧化物酶活性，并且与包括神经退行性疾病和心血管疾病在内的许多人类疾病的发病机制密切相关。cyt-c与心磷脂的相互作用模拟了cyt-c在不同溶剂环境中的部分解折叠/构象变化。cyt-c这些构象变化的动态图像对于理解它们在线粒体功能中的生理作用至关重要。因此，已经进行了原子分子动力学（MD）模拟，以研究不同溶剂（水、尿素/水、甲醇和二甲基亚砜）对凋亡cyt-c（Fe）的结构和构象的影响。我们的研究表明，蛋白质中的结构变化取决于溶剂。主要在β-折叠和α-螺旋构象上观察到结构差异，并且它们的扰动程度因溶剂而异。尽管在甲醇和二甲基亚砜中观察到β-折叠完全丧失（0%），相比之下，在水和尿素/水中观察到β-折叠保存良好（3.84%）。在甲醇（41.34%）和水中（42.46%）观察到α-螺旋含量显著降低，在二甲基亚砜中变化可忽略不计（44.25%），在尿素/水中α-螺旋含量保存良好（45.19%）。对于二甲基亚砜，电子转移关键残基之间的距离显著减小。此外，残基灵活性和构象空间的降低表明，与其他共溶剂相比，cyt-c的集体运动减少。主成分动力学分析表明，cyt-c在水、甲醇和尿素/水中的整体运动涉及三到四个特征向量，而在二甲基亚砜中涉及第一个特征向量。总体而言，我们认为cyt-c在不同溶剂中的MD模拟可以提供对凋亡早期事件中的生理作用、电子传递和过氧化物酶功能的详细微观理解，而这些是实验难以探究的。
