Abagyan R, Argos P
European Molecular Biology Laboratory, Heidelberg, Germany.
J Mol Biol. 1992 May 20;225(2):519-32. doi: 10.1016/0022-2836(92)90936-e.
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 chi 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 Tyr1 and Phe4 rings, a gamma-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.
通过分子动力学以及不同类型的蒙特卡罗方法或逐步构建方法进行构象搜索，通常旨在找到能量最低的构象。然而，这往往具有误导性，因为构象计算中使用的能量函数并不精确。例如，尽管由 Lennard-Jones 势的排斥部分定义的局部极小值的位置通常仅因函数修改而略有改变，但极小值的相对深度可能会发生显著变化。因此，应重新制定构象搜索的目的以及相应的性能标准，并找到合适的方法从搜索轨迹中提取不同的局部极小值，并在搜索空间中进行可视化。应将收敛到最低能量结构的尝试替换为努力访问一定能量范围内最大数量的不同局部能量极小值。我们始终使用这个定量标准来评估不同搜索程序的性能。为了利用模拟过程中生成的信息，创建并存储了一个低能量构象的“堆栈”。它记录了不同构象家族最佳代表的变量和访问次数。为了可视化搜索，使用了将多维行走投影到由一组参考结构定义的主平面上的方法。以甲硫氨酸脑啡肽作为结构示例，并以结合能量最小化的蒙特卡罗程序（MCM）作为基本搜索方法，我们分析了诸如温度程序、变量修改的步长、受限随机步以及对搜索困难的响应机制等不同特征对搜索效率的影响。模拟退火 MCM 在恒定温度和高温（约 600 K）下与 MCM 具有相当的效率。在每个 MCM 步骤中将侧链 χ 角的随机选择限制为最佳值（旋转异构体）并没有提高，反而降低了搜索效率。发现了两种低能量的甲硫氨酸脑啡肽构象，其 Tyr1 和 Phe4 环平行，Gly2 残基周围有一个γ-转角，并且 Phe4 和 Met5 侧链一起形成一个紧密的疏水簇，这些构象被认为是与受体或膜相互作用的可能结构候选物。
