Analysis and elimination of a bias in targeted molecular dynamics simulations of conformational transitions: application to calmodulin.
Analysis and elimination of a bias in targeted molecular dynamics simulations of conformational transitions: application to calmodulin.
复制标题
DOI：
10.1021/jp212634z
复制
发表时间：
2012-07-26
影响因子：
3.3
通讯作者：
Karplus, Martin
中科院分区：
文献类型：
--
作者：
Ovchinnikov, Victor;Karplus, Martin
回顾了在复杂生物分子系统中产生跃迁路径的流行的靶向分子动力学(TMD)方法。在典型的TMD过渡路径中，大范围的变化发生得早，小的变化往往发生得晚。因此，计算路径中事件的顺序取决于执行模拟的方向。为了确定这种偏差的来源，并提出一种没有偏差的方法，我们引入了约束公式中的TMD变体，并将其应用于蛋白质钙调蛋白中复杂的开放↔闭合跃迁。由于全局最佳匹配旋转通常是TMD方法的一部分，模拟的系统被隐式地沿着最低频率的简正模式引导，直到与这些模式相关联的大空间尺度接近目标构象。过渡的其余部分由对应于较小规模重排的较高频率模式逐步描述。避免全局最佳拟合旋转的TMD的一个直接修改是局部约束TMD(LRTMD)方法，其中偏置电势由多个TMD势构造，每个TMD势作用于蛋白质序列的一小部分相连部分。在这些元素均匀分布的情况下，得到了没有长度-尺度偏差的过渡路径。在二面角空间(DSMD)中引导MD生成的轨迹也没有长度-尺度偏差，这是一种完全避免最佳拟合旋转的方法。为了检验TMD、LRTMD和DSMD产生的路径在实际转变中的重要性，我们使用有限温度弦方法来计算每个算法产生的路径周围与过渡管相关的自由能分布。与这些路径相关的自由能垒是可比较的，这表明每条路径上的跃迁都可能以相似的概率发生。这一结果表明，需要计算广泛的路径集合，以获得对生物分子构象变化的完整描述。贡献系综的广度表明，蛋白质构象转变的能量障碍被来自大量可能路径的熵贡献所抵消。
The popular targeted molecular dynamics (TMD) method for generating transition paths in complex biomolecular systems is revisited. In a typical TMD transition path, the large-scale changes occurring early, and the small-scale changes tend to occur later. As a result, the order of events in the computed paths depends on the direction in which the simulations are performed. To identify the origin of this bias, and to propose a method in which the bias is absent, variants of TMD in the restraint formulation are introduced and applied to the complex Open↔Closed transition in the protein Calmodulin. Due to the global best-fit rotation that is typically part of the TMD method, the simulated system is guided implicitly along the lowest-frequency normal modes, until the large spatial scales associated with these modes are near the target conformation. The remaining portion of the transition is described progressively by higher-frequency modes, which correspond to smaller-scale rearrangements. A straightforward modification of TMD that avoids the global best-fit rotation is the locally restrained TMD (LRTMD) method, in which the biasing potential is constructed from a number of TMD potentials, each acting on a small connected portion of the protein sequence. With a uniform distribution of these elements, transition paths that lack the length-scale bias are obtained. Trajectories generated by steered MD in dihedral angle space (DSMD), a method that avoids best-fit rotations altogether, also lack the length-scale bias. To examine the importance of the paths generated by TMD, LRTMD, and DSMD in the actual transition, we use the finite-temperature string method to compute the free energy profile associated with a transition tube around a path generated by each algorithm. The free energy barriers associated with the paths are comparable, suggesting that transitions can occur along each route with similar probabilities. This result indicates that a broad ensemble of paths needs to be calculated to obtain a full description of conformational changes in biomolecules. The breadth of the contributing ensemble suggests that energetic barriers for conformational transitions in proteins are offset by entropic contributions that arise from a large number of possible paths.
登录
查看更多内容
影响因子：
4.4
作者：
Chipot, C;Hénin, J
通讯作者：
Hénin, J
影响因子：
2.8
作者：
FISCHER, S;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
0.9
作者：
FERIGLE, SM;WEBER, A
通讯作者：
WEBER, A
影响因子：
4.4
作者：
Bartels, C;Schaefer, M;Karplus, M
通讯作者：
Karplus, M
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M