ProteinSketch translates spatial intuition into protein design with bimanual interaction in VR

Abstract

Abstract Generative AI–based protein design can create diverse structures for desired functions but offers human designers limited control over three-dimensional architectures. We developed ProteinSketch, a bimanual virtual reality platform in which immersive backbone sketches and volumetric envelopes are directly created and translated into constraints for diffusion-based protein generation. RFdiffusion-based real-time refinement enabled interactive exploration and construction of user-specified protein topologies. Volumetric conditioning of sketched envelopes enabled high-fidelity control of anisometric geometries, confirmed by cryo–electron microscopy. These user-defined volumetric constraints enabled functional-binder design and extension of pre-existing minibinders to surfaces otherwise difficult to access within complex molecular environments using conventional design approaches. This collaborative human–AI framework integrates human spatial reasoning with generative AI for spatially directed, shape-controlled design of protein structure and function. One-sentence summary Immersive ProteinSketch embeds human spatial reasoning in AI-guided design of protein topology, shape, and function.