PartiDesign: A structure-sequence co-design paradigm for practical all-to-all biomolecules design

Abstract

Engineering interactions among biomolecules offers a route to creating new biological functions. Although unified models have advanced biomolecular structure prediction and design, efficient and controllable generation across molecular modalities remains challenging. A key challenge is to couple three-dimensional structure generation with sequence or chemical-identity design across chemically diverse systems. Here, we introduce PartiDesign, a unified structure-sequence co-design model that extends the partially latent framework of La-Proteina to proteins, nucleic acids and small molecules. PartiDesign jointly generates molecular structures and their corresponding sequences or chemical identities, while providing fine-grained control over secondary structure, chemical bonding and amino acid preferences. Across diverse benchmarks for the de novo design of proteins, nucleic acids and small molecules against specified targets, PartiDesign achieved the highest estimated successful-design throughput among the evaluated methods on most benchmarks under the adopted compute-budget protocols. Its configurable constraints further support cyclic peptide and antibody design, allowing generation to be tailored to specific structural and chemical requirements. PartiDesign was developed using 128 Huawei Ascend 910B accelerators, each with 64 GB of memory. The source code is available at https://github.com/MegaGatlingPea/PartiDesign-official, and a freely accessible web server at https://cadd.zju.edu.cn/partidesign/ enables users to generate binding partners without programming expertise. Together, these capabilities provide a versatile and accessible framework for all-to-all biomolecular design, with applications in molecular engineering and drug discovery.