Structural flexibility and protein adaptation to temperature: Molecular dynamics analysis of malate dehydrogenases of marine molluscs
Structural flexibility and protein adaptation to temperature: Molecular dynamics analysis of malate dehydrogenases of marine molluscs
复制标题
结构灵活性和蛋白质对温度的适应：海洋软体动物苹果酸脱氢酶的分子动力学分析
DOI：
10.1073/pnas.1718910115
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发表时间：
2018-02-06
影响因子：
11.1
通讯作者：
Somero, George N.
中科院分区：
文献类型：
--
作者：
Dong, Yun-wei;Liao, Ming-ling;Somero, George N.
适应不同温度的物种的同源蛋白在稳定性和功能上表现出差异，这被解释为反映了结构“灵活性”的适应性变化。然而，量化灵活性和比较蛋白质之间的灵活性仍然是一个挑战。为了解决这个问题，我们研究了温度对五属海洋软体动物不同热适应同源物的细胞质苹果酸脱氢酶（cMDH）同源物的影响，这些动物的野外体温范围接近60摄氏度。我们描述了在功能适应[温度对辅助因子KM （NADH）的影响]和结构稳定性（活性热变性率）方面的一致趋同进化模式。为了确定这些差异如何取决于整体结构的灵活性以及已知在结合和催化中重要的区域，我们进行了分子动力学模拟（MDS）分析。MDS分析显示，适应温度与热诱导的主链原子运动增加呈显著负相关[主链原子的均方根偏差（rmsd）]。单个氨基酸残基运动的均方根波动（rmsf）在整个序列中变化，在同源物中具有质量相似的模式。参与配体结合和催化的序列区域-分别称为移动区域1和2 (MR1和MR2) -显示出最大的RMSF值。热诱导的RMSF值在整个序列中的变化，重要的是，MR1和MR2的变化在冷适应物种中最大。MDS方法通过提供蛋白质灵活性的定量指标和识别灵活性发生适应性变化的序列区域，为检查酶的适应性提供了强大的工具。
Orthologous proteins of species adapted to different temperatures exhibit differences in stability and function that are interpreted to reflect adaptive variation in structural "flexibility." However, quantifying flexibility and comparing flexibility across proteins has remained a challenge. To address this issue, we examined temperature effects on cytosolic malate dehydrogenase (cMDH) orthologs from differently thermally adapted congeners of five genera of marine molluscs whose field body temperatures span a range of similar to 60 degrees C. We describe consistent patterns of convergent evolution in adaptation of function [temperature effects on KM of cofactor (NADH)] and structural stability (rate of heat denaturation of activity). To determine how these differences depend on flexibilities of overall structure and of regions known to be important in binding and catalysis, we performed molecular dynamics simulation (MDS) analyses. MDS analyses revealed a significant negative correlation between adaptation temperature and heat-induced increase of backbone atom movements [root mean square deviation (rmsd) of main-chain atoms]. Root mean square fluctuations (RMSFs) of movement by individual amino acid residues varied across the sequence in a qualitatively similar pattern among orthologs. Regions of sequence involved in ligand binding and catalysis-termed mobile regions 1 and 2 (MR1 and MR2), respectively-showed the largest values for RMSF. Heat-induced changes in RMSF values across the sequence and, importantly, in MR1 and MR2 were greatest in cold-adapted species. MDS methods are shown to provide powerful tools for examining adaptation of enzymes by providing a quantitative index of protein flexibility and identifying sequence regions where adaptive change in flexibility occurs.