ProxelGen: Generating Proteins as 3D Densities
1.ProxelGen introduces a new representation for protein structure generation: voxel-based 3D densities called "proxels", in contrast to traditional point-cloud or atomic representations. This shift allows novel conditioning capabilities and efficient generative modeling.
2.Instead of modeling proteins as lists of atoms or frames, ProxelGen treats them as 3D grids with multiple channels capturing atomic densities and chain flow. This design enables convolutional networks and efficient latent diffusion modeling.
3.ProxelGen combines a 3D CNN-based variational autoencoder (VAE) with a latent flow model to generate proxel-based protein structures. The VAE compresses spatial information, enabling a 512× reduction in dimensionality.
4.This voxel-based representation supports flexible spatial conditioning. Tasks like motif scaffolding or inpainting become simpler, as the model operates on fixed-size 3D grids and doesn’t require specifying residue numbers or positions.
5.Unlike traditional models that scale with protein length, ProxelGen scales with grid resolution. This avoids quadratic or cubic complexity from long proteins, making it efficient for large or complex designs.
6.For decoding voxel-based representations into atomistic coordinates, ProxelGen fine-tunes a small Proteina model and refines structures using a larger one, ensuring compatibility with tools like ProteinMPNN and ESMFold.
7.On unconditional protein generation, ProxelGen outperforms state-of-the-art models (e.g., Proteina) in FID, structural diversity, and contact complexity, while maintaining similar levels of designability.
8.In motif scaffolding benchmarks, especially with complex or multi-segment motifs, ProxelGen achieves higher unique success counts than all prior methods, benefiting from spatial rather than sequence-based conditioning.
9.ProxelGen also supports shape-conditioned generation. It can generate proteins that fit arbitrary 3D shapes specified as voxel masks, demonstrating high F1 scores for shape adherence without memorizing original structures.
10.To evaluate proxel quality, the authors introduce ProxCLR, a self-supervised contrastive model trained on proxel representations, and adapt Frechet Inception Distance (FID) for proxels to assess sample quality and diversity.
11.ProxelGen’s density-based framework enables new axes of control and expressivity in generative protein modeling and opens avenues for training on experimental density data (e.g., electron densities) rather than atomic models.
12.Limitations remain: generated proxels can represent fragmented chains, and enforcing global connectivity remains challenging. Improving the atomic decoder to respect motif constraints could further boost downstream performance.
📜Paper:
arxiv.org/abs/2506.19820
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