Accurate and Efficient Structural Ensemble Generation of Macrocyclic Peptides using Internal Coordinate Diffusion

Abstract

Macrocyclic peptides are an emerging therapeutic modality, yet computational approaches for accurately sampling their diverse 3D ensembles remain challenging due to their conformational diversity and geometric constraints. Here, we introduce RINGER, a diffusion-based transformer model using a redundant internal coordinate representation that generates three-dimensional conformational ensembles of macrocyclic peptides from their 2D representations. RINGER provides fast backbone and side-chain sampling while respecting key structural invariances of cyclic peptides. Through extensive benchmarking and analysis against gold-standard conformer ensembles of cyclic peptides generated with metadynamics, we demonstrate how RINGER generates both high-quality and diverse geometries at a fraction of the computational cost. Our work lays the foundation for improved sampling of cyclic geometries and the development of geometric learning methods for peptides.