Tao Huanyu, Wu Qilong, Zhao Xuejun, Lin Peicong, Huang Sheng-You
School of Physics, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, People's Republic of China.
J Cheminform. 2022 May 3;14(1):26. doi: 10.1186/s13321-022-00605-8.
Cyclic peptides formed by disulfide bonds have been one large group of common drug candidates in drug development. Structural information of a peptide is essential to understand its interaction with its target. However, due to the high flexibility of peptides, it is difficult to sample the near-native conformations of a peptide. Here, we have developed an extended version of our MODPEP approach, named MODPEP2.0, to fast generate the conformations of cyclic peptides formed by a disulfide bond. MODPEP2.0 builds the three-dimensional (3D) structures of a cyclic peptide from scratch by assembling amino acids one by one onto the cyclic fragment based on the constructed rotamer and cyclic backbone libraries. Being tested on a data set of 193 diverse cyclic peptides, MODPEP2.0 obtained a considerable advantage in both accuracy and computational efficiency, compared with other sampling algorithms including PEP-FOLD, ETKDG, and modified ETKDG (mETKDG). MODPEP2.0 achieved a high sampling accuracy with an average C[Formula: see text] RMSD of 2.20 Å and 1.66 Å when 10 and 100 conformations were considered, respectively, compared with 3.41 Å and 2.62 Å for PEP-FOLD, 3.44 Å and 3.16 Å for ETKDG, 3.09 Å and 2.72 Å for mETKDG. MODPEP2.0 also reproduced experimental peptide structures for 81.35% of the test cases when an ensemble of 100 conformations were considered, compared with 54.95%, 37.50% and 50.00% for PEP-FOLD, ETKDG, and mETKDG. MODPEP2.0 is computationally efficient and can generate 100 peptide conformations in one second. MODPEP2.0 will be useful in sampling cyclic peptide structures and modeling related protein-peptide interactions, facilitating the development of cyclic peptide drugs.
由二硫键形成的环肽一直是药物开发中一大类常见的候选药物。肽的结构信息对于理解其与靶点的相互作用至关重要。然而，由于肽具有高度的灵活性，很难对其近天然构象进行采样。在此，我们开发了我们的MODPEP方法的扩展版本，命名为MODPEP2.0，以快速生成由二硫键形成的环肽的构象。MODPEP2.0通过基于构建的旋转异构体和环骨架库将氨基酸一个一个地组装到环片段上，从头构建环肽的三维（3D）结构。在193种不同环肽的数据集上进行测试时，与包括PEP-FOLD、ETKDG和改进的ETKDG（mETKDG）在内的其他采样算法相比，MODPEP2.0在准确性和计算效率方面都获得了相当大的优势。当分别考虑10个和100个构象时，MODPEP2.0实现了较高的采样精度，平均Cα RMSD分别为2.20 Å和1.66 Å，相比之下，PEP-FOLD分别为3.41 Å和2.62 Å，ETKDG分别为3.44 Å和3.16 Å，mETKDG分别为3.09 Å和2.72 Å。当考虑100个构象的集合时，MODPEP2.0还在81.35%的测试案例中重现了实验肽结构，相比之下，PEP-FOLD为54.95%，ETKDG为37.50%，mETKDG为50.00%。MODPEP2.0计算效率高，能够在一秒钟内生成100个肽构象。MODPEP2.0将有助于对环肽结构进行采样并对相关的蛋白质-肽相互作用进行建模，促进环肽药物的开发。
