OPTIMAL PROTOCOL AND TRAJECTORY VISUALIZATION FOR CONFORMATIONAL SEARCHES OF PEPTIDES AND PROTEINS
OPTIMAL PROTOCOL AND TRAJECTORY VISUALIZATION FOR CONFORMATIONAL SEARCHES OF PEPTIDES AND PROTEINS
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DOI：
10.1016/0022-2836(92)90936-e
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发表时间：
1992-05-20
影响因子：
5.6
通讯作者：
ARGOS, P
中科院分区：
文献类型：
--
作者：
ABAGYAN, R;ARGOS, P
通过分子动力学和不同类型的蒙特卡罗或累积方法进行构象搜索通常旨在找到最低能量的构象。然而，这往往是误导，因为构象计算中使用的能量函数是不精确的。例如，虽然由伦纳-琼斯势的排斥部分定义的局部极小值的位置通常只会通过函数修改而稍微改变，但极小值的相对深度可能会发生显着变化。因此，构象搜索的目的和相应的性能标准应该重新制定，并找到适当的方法来从搜索轨迹中提取不同的局部最小值，并允许在搜索空间中可视化。在收敛到最低能量结构的尝试，应改为努力访问的最大数量的不同的本地能量最小值的能量在一定范围内。我们始终使用这个定量标准来评估不同的搜索程序的性能。为了利用模拟过程中产生的信息，创建并存储低能构象的“堆栈”。它跟踪不同构象家族的最佳代表的变量和访问次数。为了可视化搜索，使用多维行走到由一组参考结构定义的主平面上的投影。以甲硫氨酸脑啡肽为结构实例，采用能量最小化（MCM）蒙特卡罗方法作为基本搜索方法，分析了不同特征参数如温度、变量修正步长、约束随机步长以及对搜索困难的响应机制对搜索效率的影响。模拟退火MCM在恒温和高温（约600 K）下具有与MCM相当的效率。在每个MCM步骤上将侧链χ角的随机选择约束为最佳值（旋转异构体）并没有改善，而是恶化了搜索效率。发现了两种低能Met-脑啡肽构象，其具有平行的Tyrl和Phe 4环，围绕Gly 2残基的γ-转角，以及Phe 4和Met 5侧链一起形成紧密的疏水簇，并被认为是与受体或膜相互作用的可能的结构候选物。
Conformational searches by molecular dynamics and different types of Monte Carlo or build-up methods usually aim to find the lowest-energy conformation. However, this is often misleading, as the energy functions used in conformational calculations are imprecise. For instance, though positions of local minima defined by the repulsive part of the Lennard-Jones potential are usually altered only slightly by functional modification, the relative depths of the minima could change significantly. Thus, the purpose of conformational searches and, correspondingly, performance criteria should be reformulated and appropriate methods found to extract different local minima from the search trajectory and allow visualization in the search space. Attempts at convergence to the lowest-energy structure should be replaced with efforts to visit a maximum number of different local energy minima with energies within a certain range. We use this quantitative criterion consistently to evaluate performances of different search procedures. To utilize information generated in the course of simulation, a “stack” of low energy conformations is created and stored. It keeps track of variables and visit numbers for the best representatives of different conformational families. To visualize the search, projection of multidimensional walks onto a principal plane defined by a set of reference structures is used. With Met-enkephalin as a structural example and a Monte Carlo procedure combined with energy minimization (MCM) as a basic search method, we analyzed the influence on search efficiency of different characteristics as temperature schedules, the step size for variable modification, constrained random step and response mechanisms to search difficulties. Simulated annealing MCM had comparable efficiency with MCM at constant and elevated temperature (about 600 K). Constraining the randomized choice of side-chain χ angles to optimal values (rotamers) on every MCM step did not improve, but rather worsened, the search efficiency. Two low-energy Met-enkephalin conformations with parallel Tyrl and Phe4 rings, a γ-turn around the Gly2 residue, and Phe4 and Met5 side-chains forming together a compact hydrophobic cluster were found and are suggested as possible structural candidates for interaction with a receptor or a membrane.