Prediction of the structures of proteins with the UNRES force field, including dynamic formation and breaking of disulfide bonds
Prediction of the structures of proteins with the UNRES force field, including dynamic formation and breaking of disulfide bonds
复制标题
DOI：
10.1093/protein/gzh003
复制
发表时间：
2004-01-01
影响因子：
2.4
通讯作者：
Scheraga, HA
中科院分区：
文献类型：
--
作者：
Czaplewski, C;Oldziej, S;Scheraga, HA
二硫键的存在对于维持许多蛋白质的结构和功能是必不可少的。二硫键通常是在折叠过程中动态形成的。目前的蛋白质结构预测算法没有考虑这一过程，这些算法要么在结构形成后才推断二硫键的可能位置，要么在模拟折叠过程中假定二硫键是固定的。本文将构象空间退火法(CSA)和UNRES联合残基力场推广到二硫键的动态形成过程中。对二硫键半胱氨酸侧链质心之间的距离施加调和势来描述键扭曲的能量学，并为二硫键的形成增加了5.5kcal/mol的能量增益。通过引入适当的操作，二硫键的形成、断裂和重排包括在CSA搜索中；也可以通过固定的二硫键排列来进行搜索。该算法被应用于四种蛋白质：1EI0(α)、1NKL(α)、1LII(β-螺旋)和1ED0(α+β)。对于1E10，无论是在没有二硫键的情况下，还是在有二硫键的情况下，都得到了折叠正确的低能结构；但是，只有天然的二硫键排列，才获得了能量最低的结构。对于其他研究的蛋白质，正确折叠的结构是最低的(1NKL和1LII)或低能结构(1ED0)，尽管最终的二硫键排列是非天然的。结果表明，通过考虑二硫键形成的可能性，UNRES力场的预测能力得到了增强，尽管这里引入的二硫键势很少在本征位置产生二硫键。据我们所知，这是第一个基于能量预测二硫键蛋白质结构的算法，没有任何关于天然二硫化物位置或人类干预的假设。提出了提高电势的方向和寻找的方法。
The presence of disulfide bonds is essential for maintaining the structure and function of many proteins. The disulfide bonds are usually formed dynamically during folding. This process is not accounted for in present algorithms for protein-structure prediction, which either deduce the possible positions of disulfide bonds only after the structure is formed or assume fixed disulfide bonds during the course of simulated folding. In this work, the conformational space annealing (CSA) method and the UNRES united-residue force field were extended to treat dynamic formation of disulfide bonds. A harmonic potential is imposed on the distance between disulfide-bonded cysteine side-chain centroids to describe the energetics of bond distortion and an energy gain of 5.5 kcal/mol is added for disulfide-bond formation. Formation, breaking and rearrangement of disulfide bonds are included in the CSA search by introducing appropriate operations; the search can also be carried out with a fixed disulfide-bond arrangement. The algorithm was applied to four proteins: 1EI0 (alpha), 1NKL (alpha), 1LII (beta-helix) and 1ED0 (alpha + beta). For 1E10, a low-energy structure with correct fold was obtained both in the runs without and with disulfide bonds; however, it was obtained as the lowest in energy only with the native disulfide-bond arrangement. For the other proteins studied, structures with the correct fold were obtained as the lowest (1NKL and 1LII) or low-energy structures (1ED0) only in runs with disulfide bonds, although the final disulfide-bond arrangement was non-native. The results demonstrate that, by including the possibility of formation of disulfide bonds, the predictive power of the UNRES force field is enhanced, even though the disulfide-bond potential introduced here rarely produces disulfide bonds in native positions. To the best of our knowledge, this is the first algorithm for energy-based prediction of the structure of disulfide-bonded proteins without any assumption as to the positions of native disulfides or human intervention. Directions for improving the potentials and the search method are suggested.