When designing peptide ligands based on the structure of a protein receptor, it can be very useful to narrow down the possible binding positions and bound conformations of the ligand without the need to choose its amino acid sequence in advance. Here, we construct and benchmark a tool for this purpose based on a recently reported statistical energy model named SCUBA (Sidechain-Unknown Backbone Arrangement) for designing protein backbones without considering specific amino acid sequences. With this tool, backbone fragments of different local conformation types are generated and optimized with SCUBA-driven stochastic simulations and simulated annealing, and then ranked and clustered to obtain representative backbone fragment poses of strong SCUBA interaction energies with the receptor. We computationally benchmarked the tool on 111 known protein-peptide complex structures. When the bound ligands are in the strand conformation, the method is able to generate backbone fragments of both low SCUBA energies and low root mean square deviations from experimental structures of peptide ligands. When the bound ligands are helices or coils, low-energy backbone fragments with binding poses similar to experimental structures have been generated for approximately 50% of benchmark cases. We have examined a number of predicted ligand-receptor complexes by atomistic molecular dynamics simulations, in which the peptide ligands have been found to stay at the predicted binding sites and to maintain their local conformations. These results suggest that promising backbone structures of peptides bound to protein receptors can be designed by identifying outstanding minima on the SCUBA-modeled backbone energy landscape.

当根据蛋白质受体的结构设计肽配体时，缩小配体可能的结合位置和结合构象的范围非常有用，而无需提前选择其氨基酸序列。在这里，我们基于最近报道的名为 SCUBA（侧链未知主链排列）的统计能量模型构建并基准测试了一个工具，用于设计蛋白质主链，而不考虑特定的氨基酸序列。利用该工具，通过 SCUBA 驱动的随机模拟和模拟退火生成和优化不同局部构象类型的主链片段，然后进行排序和聚类以获得与受体具有强 SCUBA 相互作用能量的代表性主链片段姿势。我们在 111 种已知的蛋白质-肽复合物结构上对该工具进行了计算基准测试。当结合的配体处于链构象时，该方法能够生成具有低 SCUBA 能量和与肽配体实验结构低均方根偏差的主链片段。当结合的配体是螺旋或卷曲时，大约 50% 的基准案例生成了具有与实验结构相似的结合姿势的低能量主链片段。我们通过原子分子动力学模拟检查了许多预测的配体-受体复合物，其中发现肽配体停留在预测的结合位点并保持其局部构象。这些结果表明，通过识别 SCUBA 模型主链能量景观上的突出最小值，可以设计与蛋白质受体结合的肽的有前途的主链结构。