Charest Gabriel, Lavigne Pierre
Département de Pharmacologie, Faculté de Médecine, Université de Sherbrooke 3001, 12e Avenue Nord, Sherbrooke, Qc J1H 5N4, Canada.
Biopolymers. 2006 Feb 15;81(3):202-14. doi: 10.1002/bip.20401.
We present a minimalist approach for the modeling of the three-dimensional structure of multistranded alpha-helical coiled coils. The approach is based on empirical principles introduced by F. H. C. Crick (F. H. C. Crick, Acta Crystallogr, 1953, Vol. 6, pp. 689-697). Crick hypothesized that keeping the distance between the residues at the interacting interface of alpha-helices constant would lead to supercoiling or the formation of a coiled coil through the knobs-into-holes mode of packing. We have implemented the latter hypothesis in a simulating annealing protocol in the simple form of interhelical distance restraints (two per heptad) between Calpha at the interfacial positions and. To demonstrate the authenticity of Crick's hypothesis and the precision and accuracy of our approach, we have modeled the crystal structures of six synthetic coiled coils in dimeric, trimeric, and tetrameric states. The mean root mean square deviations (RMSDs) between the backbone atoms of the ensemble of structures calculated and those of the corresponding geometric averages is always below 0.76 A, indicating that our protocol has an excellent degree of convergence and precision. The RMSDs between the backbone atoms of each of the six geometric average structures and the backbone of the corresponding crystal structures all range between 0.43 and 0.95 A, indicative of excellent accuracy and proving the authenticity of Crick's hypothesis. Moreover, without specifying any dihedral angles, we found that in 81% of the occurrences, the most populated conformer of the side chains at positions and in the ensembles calculated were identical to those observed in the crystal structures. This shows that our simple approach, which is the simplest reported so far, can generate accurate results for the backbone and side chains. Finally, as a test case for a wider application of our approach in the field of structural proteomics, we describe the successful modeling of the overall structure of SNARE and the organization of its interfacial ionic layer known to play an important functional role.
我们提出了一种用于模拟多链α-螺旋卷曲螺旋三维结构的极简方法。该方法基于F. H. C. 克里克（F. H. C. Crick, Acta Crystallogr, 1953, Vol. 6, pp. 689 - 697）提出的经验原理。克里克推测，保持α-螺旋相互作用界面处残基之间的距离恒定，会导致超螺旋形成或通过旋钮-入-孔堆积模式形成卷曲螺旋。我们已在模拟退火协议中以界面位置处α碳原子之间螺旋间距离约束（每个七肽两个）的简单形式实现了后一种假设。为了证明克里克假设的真实性以及我们方法的精度和准确性，我们对处于二聚体、三聚体和四聚体状态的六个合成卷曲螺旋的晶体结构进行了建模。计算得到的结构集合中主链原子与相应几何平均值的主链原子之间的平均均方根偏差（RMSD）始终低于0.76 Å，表明我们的协议具有出色的收敛度和精度。六个几何平均结构中每个结构的主链原子与相应晶体结构主链之间的RMSD均在0.43至0.95 Å之间，表明具有出色的准确性并证明了克里克假设的真实性。此外，在未指定任何二面角的情况下，我们发现，在81%的情况下，计算得到的结构集合中位置处侧链最丰富的构象异构体与晶体结构中观察到的相同。这表明我们的简单方法（是迄今为止报道的最简单方法）能够为主链和侧链生成准确的结果。最后，作为我们的方法在结构蛋白质组学领域更广泛应用的一个测试案例，我们描述了SNARE整体结构及其已知发挥重要功能作用的界面离子层组织的成功建模。
