Zipping and unzipping of adenylate kinase: atomistic insights into the ensemble of open<-->closed transitions.
Zipping and unzipping of adenylate kinase: atomistic insights into the ensemble of open<-->closed transitions.
复制标题
DOI：
10.1016/j.jmb.2009.09.009
复制
发表时间：
2009-11-20
影响因子：
5.6
通讯作者：
Woolf TB
中科院分区：
文献类型：
--
作者：
Beckstein O;Denning EJ;Perilla JR;Woolf TB
腺苷酸激酶（AdK）是一种磷酸转移酶，在细胞能量平衡中起着重要作用。它经历了一个大的构象变化之间的开放和封闭状态，即使在没有底物。我们研究了apo-AdK跃迁在原子水平上的自由能计算和我们的新的动态重要性采样（DIMS）分子动力学（MD）方法。显示DIMS样品生物学相关的构象，通过比较数百个DIMS转换到AdK晶体结构中间体的集合来验证。模拟揭示了在原子的细节铰链区部分和间歇性地展开在过渡期间。保守的盐桥被认为具有重要的结构和动态的作用，特别是四个离子键被确定为开放的顺序，拉链一样的方式，从而主导了自由能景观的过渡。封闭和开放构象之间的转变只需要克服适度的自由能势垒。出乎意料的是，封闭和开放状态包含广泛的自由能盆地，其中包含的构象不同域铰链运动高达40 °。这些扩展状态的意义进行了讨论，最近的实验FRET测量。综上所述，这些结果表明，少量的合作关键相互作用可以塑造酶的整体动力学，并建议一个“全有或全无”的机制，打开和关闭的AdK。我们高效的DIMS-MD计算机模拟方法可以提供一个功能重要的大分子过渡的详细图片，从而有助于解释和建议实验，以探测动态蛋白质，如AdK的构象景观。
Adenylate kinase (AdK), a phosphotransferase enzyme, plays an important role in cellular energy homeostasis. It undergoes a large conformational change between an open and a closed state, even in the absence of substrate. We investigate the apo-AdK transition at the atomic level both with free energy calculations and our new dynamic importance sampling (DIMS) molecular dynamics (MD) method. DIMS is shown to sample biologically relevant conformations as verified by comparing an ensemble of hundreds of DIMS transitions to AdK crystal structure intermediates. The simulations reveal in atomic detail how hinge regions partially and intermittently unfold during the transition. Conserved salt bridges are seen to have important structural and dynamic roles; in particular four ionic bonds are identified that open in a sequential, zipper-like fashion and thus dominate the free energy landscape of the transition. Transitions between the closed and open conformations only have to overcome moderate free energy barriers. Unexpectedly, the closed and open state encompass broad free energy basins that contain conformations differing in domain hinge motions by up to 40°. The significance of these extended states is discussed in relation to recent experimental FRET measurements. Taken together, these results demonstrate how a small number of cooperative key interactions can shape the overall dynamics of an enzyme and suggest an “all-or-nothing” mechanism for the opening and closing of AdK. Our efficient DIMS-MD computer simulation approach can provide a detailed picture of a functionally important macromolecular transition and thus help to interpret and suggest experiments to probe the conformational landscape of dynamic proteins such as AdK.
登录
查看更多内容
影响因子：
5.6
作者：
GERSTEIN, M;SCHULZ, G;CHOTHIA, C
通讯作者：
CHOTHIA, C
影响因子：
2.9
作者：
Berry, MB;Bae, EY;Phillips, GN
通讯作者：
Phillips, GN
影响因子：
3.4
作者：
Kantarci-Carsibasi, Nigar;Haliloglu, Turkan;Doruker, Pemra
通讯作者：
Doruker, Pemra
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.1073/pnas.0708600104
发表时间：
2007-11-13
影响因子：
11.1
作者：
Hanson, Jeffrey A.;Duderstadt, Karl;Yang, Haw
通讯作者：
Yang, Haw