Srinivasan S, March C J, Sudarsanam S
Department of Protein Chemistry, Immunex Corporation, Seattle, Washington 98101.
Protein Sci. 1993 Feb;2(2):277-89. doi: 10.1002/pro.5560020216.
We present an automated method incorporated into a software package, FOLDER, to fold a protein sequence on a given three-dimensional (3D) template. Starting with the sequence alignment of a family of homologous proteins, tertiary structures are modeled using the known 3D structure of one member of the family as a template. Homologous interatomic distances from the template are used as constraints. For nonhomologous regions in the model protein, the lower and the upper bounds for the interatomic distances are imposed by steric constraints and the globular dimensions of the template, respectively. Distance geometry is used to embed an ensemble of structures consistent with these distance bounds. Structures are selected from this ensemble based on minimal distance error criteria, after a penalty function optimization step. These structures are then refined using energy optimization methods. The method is tested by simulating the alpha-chain of horse hemoglobin using the alpha-chain of human hemoglobin as the template and by comparing the generated models with the crystal structure of the alpha-chain of horse hemoglobin. We also test the packing efficiency of this method by reconstructing the atomic positions of the interior side chains beyond C beta atoms of a protein domain from a known 3D structure. In both test cases, models retain the template constraints and any additionally imposed constraints while the packing of the interior residues is optimized with no short contacts or bond deformations. To demonstrate the use of this method in simulating structures of proteins with nonhomologous disulfides, we construct a model of murine interleukin (IL)-4 using the NMR structure of human IL-4 as the template. The resulting geometry of the nonhomologous disulfide in the model structure for murine IL-4 is consistent with standard disulfide geometry.
我们提出了一种集成在软件包FOLDER中的自动化方法，用于在给定的三维（3D）模板上折叠蛋白质序列。从一组同源蛋白质的序列比对开始，使用该家族中一个成员的已知3D结构作为模板对三级结构进行建模。来自模板的同源原子间距离用作约束条件。对于模型蛋白质中的非同源区域，原子间距离的下限和上限分别由空间位阻约束和模板的球状尺寸决定。距离几何法用于嵌入与这些距离界限一致的一组结构。在经过惩罚函数优化步骤后，根据最小距离误差标准从这组结构中选择结构。然后使用能量优化方法对这些结构进行优化。通过以人血红蛋白的α链为模板模拟马血红蛋白的α链，并将生成的模型与马血红蛋白α链的晶体结构进行比较，对该方法进行了测试。我们还通过从已知的3D结构重建蛋白质结构域Cβ原子以外的内侧链的原子位置，测试了该方法的堆积效率。在这两个测试案例中，模型保留了模板约束和任何额外施加的约束，同时内部残基的堆积得到了优化，没有短接触或键变形。为了证明该方法在模拟具有非同源二硫键的蛋白质结构中的应用，我们以人白细胞介素（IL）-4的NMR结构为模板构建了小鼠IL-4的模型。小鼠IL-4模型结构中非同源二硫键的最终几何形状与标准二硫键几何形状一致。
