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首页> 外文期刊>Journal of Molecular Biology >Design of protein-ligand binding based on the molecular-mechanics energy model.
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Design of protein-ligand binding based on the molecular-mechanics energy model.

机译：基于分子力学能量模型的蛋白质-配体结合设计。

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While the molecular-mechanics field has standardized on a few potential energy functions, computational protein design efforts are based on potentials that are unique to individual laboratories. Here we show that a standard molecular-mechanics potential energy function without any modifications can be used to engineer protein-ligand binding. A molecular-mechanics potential is used to reconstruct the coordinates of various binding sites with an average root-mean-square error of 0.61 A and to reproduce known ligand-induced side-chain conformational shifts. Within a series of 34 mutants, the calculation can always distinguish between weak (K(d)>1 mM) and tight (K(d)<10 microM) binding sequences. Starting from partial coordinates of the ribose-binding protein lacking the ligand and the 10 primary contact residues, the molecular-mechanics potential is used to redesign a ribose-binding site. Out of a search space of 2 x 10(12) sequences, the calculation selects a point mutant of the native protein as the topsolution (experimental K(d)=17 microM) and the native protein as the second best solution (experimental K(d)=210 nM). The quality of the predictions depends on the accuracy of the generalized Born electrostatics model, treatment of protonation equilibria, high-resolution rotamer sampling, a final local energy minimization step, and explicit modeling of the bound, unbound, and unfolded states. The application of unmodified molecular-mechanics potentials to protein design links two fields in a mutually beneficial way. Design provides a new avenue for testing molecular-mechanics energy functions, and future improvements in these energy functions will presumably lead to more accurate design results.
机译：尽管分子力学领域已经对一些潜在的能量函数进行了标准化，但是蛋白质的计算设计工作是基于各个实验室独有的潜力。在这里，我们显示了没有任何修改的标准分子力学势能函数可用于工程化蛋白质-配体结合。分子力学潜能用于重建平均均方根误差为0.61 A的各种结合位点的坐标，并重现已知的配体诱导的侧链构象位移。在一系列34个突变体中，计算始终可以区分弱（K（d）> 1 mM）和紧密（K（d）<10 microM）结合序列。从缺少配体的核糖结合蛋白的部分坐标和10个主要接触残基开始，利用分子力学潜力重新设计核糖结合位点。从2 x 10（12）个序列的搜索空间中，计算选择天然蛋白质的点突变体作为最高解（实验K（d）= 17 microM），将天然蛋白质作为次佳解决方案（实验K（ d）= 210 nM）。预测的质量取决于广义Born静电模型的精度，质子平衡的处理，高分辨率旋转异构体采样，最终的局部能量最小化步骤以及结合，未结合和未折叠状态的显式建模。未经修饰的分子力学潜能在蛋白质设计中的应用以互利的方式联系了两个领域。设计提供了一种测试分子力学能量函数的新途径，这些能量函数的未来改进可能会导致更准确的设计结果。

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