Clore G M, Brünger A T, Karplus M, Gronenborn A M
J Mol Biol. 1986 Oct 5;191(3):523-51. doi: 10.1016/0022-2836(86)90146-4.
The applicability of restrained molecular dynamics for the determination of three-dimensional protein structures on the basis of short interproton distances (less than 4 A) that can be realistically determined from nuclear magnetic resonance measurements in solution is assessed. The model system used is the 1.2 A resolution crystal structure of the 46 residue protein crambin, from which a set of 240 approximate distance restraints, divided into three ranges (2.5 +/- 0.5, 3.0+0.5(-1.0) and 4 +/- 1 A), is derived. This interproton distance set comprises 159 short-range ([i-j] less than or equal to 5) and 56 ([i-j] greater than 5) long-range inter-residue distances and 25 intra-residue distances. Restrained molecular dynamics are carried out using a number of different protocols starting from two initial structures: a completely extended beta-strand; and an extended structure with two alpha-helices in the same positions as in the crystal structure (residues 7 to 19, and 23 to 30) and all other residues in the form of extended beta-strands. The root-mean-square (r.m.s.) atomic differences between these two initial structures and the crystal structure are 43 A and 23 A, respectively. It is shown that, provided protocols are used that permit the secondary structure elements to form at least partially prior to folding into a tertiary structure, convergence to the correct final structure, both globally and locally, is achieved. The r.m.s. atomic differences between the converged restrained dynamics structures and the crystal structure range from 1.5 to 2.2 A for the backbone atoms and from 2.0 to 2.8 A for all atoms. The r.m.s. atomic difference between the X-ray structure and the structure obtained by first averaging the co-ordinates of the converged restrained dynamics structures is even smaller: 1.0 A for the backbone atoms and 1.6 A for all atoms. These results provide a measure with which to judge future experimental results on proteins whose crystal structures are unknown. In addition, from an examination of the dynamics trajectories, it is shown that the convergence pathways followed by the various simulations are different.
评估了受限分子动力学在基于短质子间距离（小于4埃）确定三维蛋白质结构方面的适用性，这些短质子间距离可通过溶液中的核磁共振测量实际确定。所使用的模型系统是46个残基的蛋白克拉宾的1.2埃分辨率晶体结构，从中得出一组240个近似距离限制，分为三个范围（2.5±0.5、3.0 + 0.5(-1.0)和4±1埃）。该质子间距离集包括159个短程（[i - j]小于或等于5）和56个（[i - j]大于5）长程残基间距离以及25个残基内距离。受限分子动力学使用多种不同方案从两个初始结构开始进行：一个完全伸展的β链；以及一个伸展结构，其中两个α螺旋处于与晶体结构相同的位置（残基7至19以及23至30），所有其他残基为伸展的β链形式。这两个初始结构与晶体结构之间的均方根（r.m.s.）原子差异分别为43埃和23埃。结果表明，只要使用允许二级结构元件在折叠成三级结构之前至少部分形成的方案，就能在全局和局部上收敛到正确的最终结构。收敛后的受限动力学结构与晶体结构之间的均方根原子差异对于主链原子为1.5至2.2埃，对于所有原子为2.0至2.8埃。X射线结构与通过首先对收敛后的受限动力学结构的坐标进行平均得到的结构之间的均方根原子差异甚至更小：对于主链原子为1.0埃，对于所有原子为1.6埃。这些结果提供了一种衡量标准，可用于判断未来关于晶体结构未知的蛋白质的实验结果。此外，通过对动力学轨迹的检查表明，各种模拟所遵循的收敛途径是不同的。
