Protein generation with embedding learning for motif diversification

A fundamental challenge in protein design is the trade-off between generating structural diversity while preserving motif biological function. Current state-of-the-art methods, such as partial diffusion in RFdiffusion, often fail to resolve this trade-off: small perturbations yield motifs nearly identical to the native structure, whereas larger perturbations violate the geometric constraints necessary for biological function. We introduce Protein Generation with Embedding Learning (PGEL), a general framework that learns high-dimensional embeddings encoding sequence and structural features of a target motif in the representation space of a diffusion model's frozen denoiser, and then enhances motif diversity by introducing controlled perturbations in the embedding space. PGEL is thus able to loosen geometric constraints while satisfying typical design metrics, leading to more diverse yet viable structures. We demonstrate PGEL on three representative cases: a monomer, a protein-protein interface, and a cancer-related transcription factor complex. In all cases, PGEL achieves greater structural diversity, better designability, and improved self-consistency, as compared to partial diffusion. Our results establish PGEL as a general strategy for embedding-driven protein generation allowing for systematic, viable diversification of functional motifs.

The unbearable lightness of Restricted Boltzmann Machines: Theoretical Insights and Biological Applications

Restricted Boltzmann Machines are simple yet powerful neural networks. They can be used for learning structure in data, and are used as a building block of more complex neural architectures. At the same time, their simplicity makes them easy to use, amenable to theoretical analysis, yielding interpretable models in applications. Here, we focus on reviewing the role that the activation functions, describing the input-output relationship of single neurons in RBM, play in the functionality of these models. We discuss recent theoretical results on the benefits and limitations of different activation functions. We also review applications to biological data analysis, namely neural data analysis, where RBM units are mostly taken to have sigmoid activation functions and binary units, to protein data analysis and immunology where non-binary units and non-sigmoid activation functions have recently been shown to yield important insights into the data. Finally, we discuss open problems addressing which can shed light on broader issues in neural network research.