ICM - A NEW METHOD FOR PROTEIN MODELING AND DESIGN - APPLICATIONS TO DOCKING AND STRUCTURE PREDICTION FROM THE DISTORTED NATIVE CONFORMATION
ICM - A NEW METHOD FOR PROTEIN MODELING AND DESIGN - APPLICATIONS TO DOCKING AND STRUCTURE PREDICTION FROM THE DISTORTED NATIVE CONFORMATION
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DOI：
10.1002/jcc.540150503
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发表时间：
1994-05-01
影响因子：
3
通讯作者：
KUZNETSOV, D
中科院分区：
文献类型：
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作者：
ABAGYAN, R;TOTROV, M;KUZNETSOV, D
描述了一种用于任意固定多分子系统的通用建模操作和全局能量优化的有效方法，又称为ICM。它的目标是蛋白质结构预测、同源建模、分子对接、核磁共振结构测定和蛋白质设计。该方法使用并进一步发展了先前介绍的模拟生物分子结构的方法，其中键长度、键角和扭转角被认为是自变量，它们的任何子集都是固定的。在这里，我们简化和推广了系统的基本描述，引入了可变的二面体相角，允许分子之间的任意连接和扭角的常规定义。给出了关于系统拓扑树内变量的能量导数的计算方法和可达表面的快速计算方法。提出了多维可变约束来表示蛋白质中扭角分布的统计信息。为了将复能项如溶剂化能和静电学纳入到结构预测过程中，提出并证明了一种“双能”蒙特卡罗最小化过程，该过程在随机步骤的最小化阶段省略了这些项，并将其与马尔可夫链中的先前构象进行比较。将ICM方法成功地应用于分子对接问题。该程序从完全随机构型出发，找到亮氨酸拉链结构域中两个刚性螺旋的正确平行排列，作为最低能量构象(0.5埃均方根，RMS，与自然结构的偏差)。具有反平行螺旋或错开一圈螺旋的结构的能量分别高出约7千卡/摩尔和9千卡/摩尔。还尝试了软对接。允许侧链灵活性的对接程序也收敛到并行构型，从单独优化的螺旋开始。为了证明内部坐标方法与笛卡尔方法不同的结构预测方法的合理性，我们研究了南瓜种子胰蛋白酶抑制剂天然结构周围的能量超曲面。从最优构象随机扭曲到均方根偏差2.2埃或角均方根偏差10度的扭角最小化在大多数情况下恢复了天然构象。相比之下，笛卡尔坐标最小化没有达到最小的偏差，偏差为0.3埃或2度。我们的结论是，解决蛋白质折叠问题的最有前景的详细方法将包括一些粗略的全局采样策略和扭转坐标空间中的局部能量最小化。(C)1994年，John Wiley&Sons，Inc.
An efficient methodology, further referred to as ICM, for versatile modeling operations and global energy optimization on arbitrarily fixed multimolecular systems is described. It is aimed at protein structure prediction, homology modeling, molecular docking, nuclear magnetic resonance (NMR) structure determination, and protein design. The method uses and further develops a previously introduced approach to model biomolecular structures in which bond lengths, bond angles, and torsion angles are considered as independent variables, any subset of them being fixed. Here we simplify and generalize the basic description of the system, introduce the variable dihedral phase angle, and allow arbitrary connections of the molecules and conventional definition of the torsion angles. Algorithms for calculation of energy derivatives with respect to internal variables in the topological tree of the system and for rapid evaluation of accessible surface are presented. Multidimensional variable restraints are proposed to represent the statistical information about the torsion angle distributions in proteins. To incorporate complex energy terms as solvation energy and electrostatics into a structure prediction procedure, a ''double-energy'' Monte Carlo minimization procedure in which these terms are omitted during the minimization stage of the random step and included for the comparison with the previous conformation in a Markov chain is proposed and justified. The ICM method is applied successfully to a molecular docking problem. The procedure finds the correct parallel arrangement of two rigid helixes from a leucine zipper domain as the lowest-energy conformation (0.5 Angstrom root mean square, rms, deviation from the native structure) starting from completely random configuration. Structures with antiparallel helixes or helixes staggered by one helix turn had energies higher by about 7 or 9 kcal/mol, respectively. Soft docking was also attempted. A docking procedure allowing side-chain flexibility also converged to the parallel configuration, starting from the helixes optimized individually. To justify an internal coordinate approach to the structure prediction as opposed to a Cartesian one, energy hypersurfaces around the native structure of the squash seeds trypsin inhibitor were studied. Torsion angle minimization from the optimal conformation randomly distorted up to the rms deviation of 2.2 Angstrom or angular rms deviation of 10 degrees restored the native conformation in most cases. In contrast, Cartesian coordinate minimization did not reach the minimum from deviations as small as 0.3 Angstrom or 2 degrees. We conclude that the most promising detailed approach to the protein-folding problem would consist of some coarse global sampling strategy combined with the local energy minimization in the torsion coordinate space. (C) 1994 by John Wiley & Sons, Inc.