PRIME: A Pretrained Representation-Induced Model for 3D Molecules in De Novo Binder Design
Biomolecular binder design for peptides and antibodies requires generating diverse candidates that satisfy stringent three-dimensional geometric constraints while enabling affinity-oriented exploration under strong structural priors. In current generative models, the effective search space for structurally feasible binders is severely constrained, as the complexity of biochemical interactions is not explicitly encoded into a semantically grounded representation of viable molecular manifolds. To address this challenge, we propose Pretrained Representation Induced Molecular gEneration (PRIME), a unified generative framework for three-dimensional binder design across peptides and antibodies. PRIME grounds stochastic generation on frozen large-scale pretrained structural representations, inheriting robust physical priors to ensure structural feasibility without training a manifold from scratch. However, defining a feasible space alone is insufficient for effective exploration. Under commonly used isotropic perturbations, chain topology is ignored, allowing local noise to propagate into global structural distortions. To enable controlled exploration within the feasible space, we introduce Semantics-Preserving Exploratory Sampling (SPES), which integrates Graph Laplacian Spectral Noise to respect chain connectivity and Conditional Freedom Modulation to dynamically balance exploration with fidelity. By aligning stochastic exploration with structural semantics, PRIME enables diversity-enhanced generation without sacrificing geometric validity under the reported structural metrics, improving the empirical exploration--fidelity trade-off. PRIME achieves state-of-the-art performance on unified peptide and antibody benchmarks, effectively reconciling geometric validity with functional optimization under computational proxy metrics. The source code is available at https://github.com/simplaj/PRIME.