Solution structures of proteins from NMR data and modeling: alternative folds for neutrophil peptide 5.
Solution structures of proteins from NMR data and modeling: alternative folds for neutrophil peptide 5.
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来自 NMR 数据和建模的蛋白质溶液结构：中性粒细胞肽 5 的替代折叠。
DOI：
10.1021/bi00450a017
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发表时间：
1989
期刊：
影响因子：
2.9
通讯作者：
Pardi,A
中科院分区：
文献类型：
--
作者：
Levy,RM;Bassolino,DA;Kitchen,DB;Pardi,A
科罗拉多大学博尔德分校化学与生物化学系，博尔德，科罗拉多州 80309 收稿日期：1989 年 4 月 20 日；修订稿于 1989 年 7 月 14 日收到摘要：最近报道了溶液中中性粒细胞肽 5 的结构（Pardi 等人，1988）。通过使用距离几何算法和从 2D NMR 数据获得的 107 个质子间距离约束来完成结构确定。在距离几何方程的八个独立解中，多肽主链的整体折叠是相同的，并且叠加结构的主链原子之间的均方根（rms）偏差很小（〜2.4μ）。在本文中，我们报告了通过使用新的结构生成算法获得的附加 NP-5 结构：扭转角空间中的蒙特卡洛搜索。这些结构与距离几何结构有很大的均方根主干偏差（~ 5.0 Á）。主干拓扑与距离几何结构以及彼此之间在显着方面有所不同。发现结构是部分或全部折叠的伪镜像，对应于首先通过距离几何过程获得的结构。对于小蛋白质，在伪镜像中区分正确结构的问题可能比以前认识到的要大。当从新颖的蒙特卡洛结构构建的一组测试距离约束用作距离几何算法的输入时，所得结构的折叠与目标的折叠不对应。结果还表明，先前接受的用于定义从 NMR 数据生成的肽结构的准确性和精密度的标准（距离几何方程的多个解之间的均方根偏差的大小）是不够的。对不同折叠拓扑对应的结构进行了能量分析。通过最小化和分子动力学细化获得的分子力学能量为消除某些替代结构提供了足够的信息。在仔细比较不同试验结构与实验数据的基础上，得出结论：最初报道的NP-5肽折叠与数据最为一致。与低能量和小总距离违规结构相对应的替代折叠被排除，因为对于这种折叠，预测的 NOE 没有在实验中观察到。在过去几年中，使用来自 2D NMR 数据的信息确定溶液中蛋白质的结构已经取得了巨大进展（Wüthrich，1986）。结构确定过程有两个概念上不同的步骤：(1) 使用 NMR 数据生成一组主要由核间距离范围组成的结构约束，以及 (2) 使用适当的计算机算法根据这些约束确定三维结构。距离几何算法是第一个成功的算法
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309 Received April 20, 1989; Revised Manuscript Received July 14, 1989 abstract: The structure of neutrophil peptide 5 in solution has recently been reported (Pardi et al., 1988). The structure determination was accomplished by using a distance geometry algorithm and 107 interproton distance constraints obtained from 2D NMR data. In each of the eight independent solutions to the distance geometry equations, the overall fold of the polypeptide backbone was identical and the root mean square (rms) deviation between backbone atoms of the superimposed structures was small (~ 2.4 Á). In this paper we report additional NP-5 structures obtained by using a new structure generation algorithm: a Monte Carlo search in torsion angle space. These structures have a large rms backbone deviation from thedistance geometry structures (~ 5.0 Á). The backbone topologies differ in significant respects from the distance geometry structures and from each other. Structures are found that are pseudo mirror images of part or all of the fold corresponding to that first obtained with the distance geometry procedure. For small proteins, the problem of distinguishing the correct structure among pseudo mirror images is likely to be greater than previously recognized. When a set of test distance constraints constructed from a novel Monte Carlo structure is used as input in the distance geometry algorithm, the fold of the resulting structure does not correspond to that of the target. The results also demonstrate that the previously accepted criteria (the magnitude of the rms deviation between multiple solutions of the distance geometry equations) for defining the accuracy and precision of a peptide structure generated from NMR data are inadequate. An energetic analysis of structures corresponding to the different folding topologies has been carried out. The molecular mechanics energies obtained by minimization and molecular dynamics refinement provide sufficient information to eliminate certain alternative structures. On the basis of a careful comparison of the different trial structures with the experimental data, it is concluded that the NP-5 peptide fold which was originally reported is most consistent with the data. An alternative fold corresponding to structures with low energies and small total distance violations is ruled out because for this fold predicted NOEs are not observed experimentally.During the past few years enormous progress has been achieved in the determination of the structure of proteins in solution using information derived from 2D NMR data (Wüthrich, 1986). There are two conceptually distinct steps in the structure determination process:(1) the use of the NMR data to generate a set of structural constraints that consists primarily of internuclear distance ranges and (2) the determination of three-dimensional structures based on these constraints using an appropriate computer algorithm. The distance geometry algorithm was the first algorithm suc-