Accurate modeling of protein-peptide interactions is essential for understanding fundamental biological processes and designing peptide-based drugs. However, predicting the complex structures of these interactions remains challenging, primarily due to the high conformational flexibility of peptides. To support a fair and systematic evaluation of recent deep learning (DL) approaches, we introduce PepPCBench, a benchmarking framework tailored to assess protein folding neural networks (PFNNs) in protein-peptide complex prediction. As part of this framework, we curated PepPCSet, a data set of 261 experimentally resolved complexes with peptides ranging from 5 to 30 residues. We benchmark five full-atom PFNNs, including AlphaFold3 (AF3), AlphaFold-Multimer (AFM), Chai-1, HelixFold3 (HF3), and RoseTTAFold-All-Atom (RFAA), using comprehensive evaluation metrics. Our benchmarking reveals meaningful performance differences among these methods and highlights the influence of peptide length, conformational flexibility, and training set similarity on prediction accuracy. While AF3 shows strong performance in structure prediction, further analysis indicates that confidence metrics correlate poorly with experimental binding affinities, underscoring the need for improved scoring strategies and generalizability. By providing a reproducible and extensible framework, PepPCBench enables a robust evaluation of PFNN-based methods and supports their continued development for peptide-protein structure prediction.
Silong Zhai, Huifeng Zhao, Jike Wang et al.· Journal of Chemical Informat...· 13 citations· ⚡1
The integration of organic synthesis with enzymatic catalysis offers a promising route toward efficient and sustainable construction of complex molecules. While organic synthesis enables diverse transformations, enzymatic catalysis enhances stereoselectivity under mild conditions, improving cost-effectiveness and environmental impact. However, current enzymatic synthesis planning algorithms face challenges in formulating robust hybrid organic–enzymatic strategies. Key issues include the difficulty in devising hybrid planning approaches and the reliance on template-based enzyme recommendations, which limits their adaptability across diverse scenarios. Here we show ChemEnzyRetroPlanner, an open-source hybrid synthesis planning platform that combines organic and enzymatic strategies with AI-driven decision-making. The platform features advanced computational modules, including hybrid retrosynthesis planning, reaction condition prediction, plausibility evaluation, enzymatic reaction identification, enzyme recommendation, and in silico validation of enzyme active sites. A central innovation is the RetroRollout* search algorithm, which outperforms existing tools in planning synthesis routes for organic compounds and natural products across multiple datasets. ChemEnzyRetroPlanner provides an intuitive graphical interface and programmatic APIs for scalability, while leveraging the chain-of-thought strategy and the Llama3.1 model to autonomously activate hybrid synthesis strategies for diverse scenarios. The results indicate that this fully automated, open-source system holds potential value for improving the efficiency and sustainability of molecular synthesis. The integration of organic and enzymatic synthesis enhances molecule construction efficiency. Here, the authors present ChemEnzyRetroPlanner, an AI-driven platform for automated hybrid synthesis planning, improving synthesis route efficiency and sustainability.