ACOT1蛋白突变的分子动力学研究  

Mutation research on ACOT1 protein based on molecular dynamics

作　　者：张丽杰[1] 李雪楠[1] 李昊阳[1] 周家蓬[1] 陈禹保[1] 

机构地区：[1]北京市计算中心,北京100094

出　　处：《计算机与应用化学》2014年第6期727-731,共5页Computers and Applied Chemistry

基　　金：北京市科学技术研究院海外人才项目(OTP-2011-011;OTP-2012-011)

摘　　要：酰基辅酶硫酯酶(Acyl-CoA thioesterases,ACOTs),也被称作酰基辅酶A水解酶,是一类能够水解酰基辅酶A酯类水解的酶,在脂肪酸的代谢中起着重要的作用。文中通过将序列分析得到的ACOT1的有害突变序列(ACOT1_MULT)和野生型序列利用同源建模的方法得到了相应的蛋白结构,并利用分子动力学模拟的方法研究了突变氨基酸对蛋白结构造成的影响。研究结果发现:突变蛋白在分子动力学过程中活性中心上面的"盖子"(LEU374-SER380)区域打开,而野生型一直处于关闭状态。通过对氢键和疏水作用的分析发现,突变位置的氨基酸(ALA189THR)与蛋白序列中的GLY169形成了新的氢键,突变残基附近的氢键也发生了很大的变化,导致了邮水解酶区域的第3个β折叠的末端Loop区(160Loop)朝着外侧的亲水性区域拉伸。160Loop区域的变化使得它与"盖子"区域之间的疏水相互作用消失,"盖子"区域的稳定性下降,并最终导致了"盖子"的打开。该结果对ACOT1蛋白相关的人类免疫病毒缺陷疾病和附睾炎等疾病的发病机理的研究具有很好的借鉴作用,同时也为基于该活性区域的抑制剂筛选工作提供了新的靶点。Acyl-CoA thioesterases （ACOTs）,also known as acyl-CoA hydrolases,catalyze the hydrolysis of CoA esters of many compounds.These enzymes play an important role in lipid metabolism.This research build two protein model using the mutation sequence （ACOT1_MULT） and the wild type sequence（ACOT1） by homology modeling,and analyzed the impact on the protein structure through molecule dynamics.The results show that the ＂lid＂ （residues between LEU374 and SER380） region located at the top of the active site open during the molecule dynamics in ACOT1_MULT system,however,the corresponding region in the ACOT1 system remain closed during the molecule dynamics.By analyzing the hydrogen bond and hydrophobic effect in the ACOT1_MULT system,we found that the mutation residue forms new hydrogen bond with the GLY169 residue,there are also large hydrogen bonds fluctuation near the mutation site.These changes lead to the 160Loop which located at the end of the third β sheet in α/β hydrolases site stretches toward the hydrophilic region.The change in the 160Loop region result in the disappearance of hydrophobic effect between it and the ＂lid＂ region and the stability decline of this region,which result in the open of the ＂lid＂ region eventually.The study have a good reference for research on pathogenesis of human immunodeficiency virus infectious disease and epididymitis,whilst for screening inhibitors based on the new active site.

关 键 词：ACOT1 ACOT1_MULT 序列突变 氢键 疏水相互作用 分子动力学模拟 

分 类 号：O641[理学—物理化学]