Aszódi A, Taylor W R
Division of Mathematical Biology, National Institute for Medical Research, London, UK.
Fold Des. 1996;1(5):325-34. doi: 10.1016/S1359-0278(96)00048-X.
Unknown protein structures can be predicted from known structures (the scaffolds) with sequences sufficiently homologous to that of the target, based on the observation that similar sequences usually adopt the same fold. When structural equivalences between residues in the scaffold and target proteins are expressed in terms of conserved interatomic distances, the resulting 'distance geometry' representation provides an elegant mechanism for simultaneous restraint satisfaction and bias-free conformation space exploration.
We present a homology modelling algorithm based on distance geometry that relies on the gradual projection of simple model chain coordinates into Euclidean spaces with decreasing dimensionality. The similarity between the unknown target structure and the scaffold proteins with known structures was described by mapping secondary structure assignments and specific distance restraints between C alpha atoms onto the model through a multiple alignment. This information was complemented by additional restraints derived from stereochemical considerations and other general aspects of protein structure such as hydrophobic core formation or the absence of tangled mainchains.
The method was capable of quickly locating the correct fold even from an alignment with modest average conservation indicating that it could serve as a fast tool for obtaining correct low-resolution starting conformations for detailed refinement.
基于相似序列通常采用相同折叠方式这一观察结果，对于具有与目标序列足够同源的已知结构（支架），未知蛋白质结构可以从这些已知结构中预测出来。当支架蛋白和目标蛋白中残基之间的结构等效性用保守的原子间距离来表示时，所得到的“距离几何”表示为同时满足约束条件和无偏差地探索构象空间提供了一种优雅的机制。
我们提出了一种基于距离几何的同源建模算法，该算法依赖于将简单模型链坐标逐步投影到维度不断降低的欧几里得空间中。通过多重比对将二级结构归属以及Cα原子之间的特定距离约束映射到模型上，以此来描述未知目标结构与具有已知结构的支架蛋白之间的相似性。从立体化学考虑以及蛋白质结构的其他一般方面（如疏水核心形成或不存在缠结的主链）得出的额外约束对这些信息起到了补充作用。
该方法即使从平均保守性一般的比对中也能够快速定位正确的折叠方式，这表明它可以作为一种快速工具，用于获得正确的低分辨率起始构象以便进行详细的优化。
