Enzymes are genetically encoded biocatalysts capable of accelerating chemical reactions. How can we automatically design functional enzymes? In this paper, we propose EnzyGen, an approach to learn a unified model to design enzymes across all functional families. Our key idea is to generate an enzyme's amino acid sequence and their three-dimensional (3D) coordinates based on functionally important sites and substrates corresponding to a desired catalytic function. These sites are automatically mined from enzyme databases. EnzyGen consists of a novel interleaving network of attention and neighborhood equivariant layers, which captures both long-range correlation in an entire protein sequence and local influence from nearest amino acids in 3D space. To learn the generative model, we devise a joint training objective, including a sequence generation loss, a position prediction loss and an enzyme-substrate interaction loss. We further construct EnzyBench, a dataset with 3157 enzyme families, covering all available enzymes within the protein data bank (PDB). Experimental results show that our EnzyGen consistently achieves the best performance across all 323 testing families, surpassing the best baseline by 10.79% in terms of substrate binding affinity. These findings demonstrate EnzyGen's superior capability in designing well-folded and effective enzymes binding to specific substrates with high affinities. Our code, model and dataset are provided at https://github.com/LeiLiLab/EnzyGen.

Deep generative models are commonly used for generating images and text. Interpretability of these models is one important pursuit, other than the generation quality. Variational auto-encoder (VAE) with Gaussian distribution as prior has been successfully applied in text generation, but it is hard to interpret the meaning of the latent variable. To enhance the controllability and interpretability, one can replace the Gaussian prior with a mixture of Gaussian distributions (GM-VAE), whose mixture components could be related to hidden semantic aspects of data. In this paper, we generalize the practice and introduce DEM-VAE, a class of models for text generation using VAEs with a mixture distribution of exponential family. Unfortunately, a standard variational training algorithm fails due to the \emph{mode-collapse} problem. We theoretically identify the root cause of the problem and propose an effective algorithm to train DEM-VAE. Our method penalizes the training with an extra \emph{dispersion term} to induce a well-structured latent space. Experimental results show that our approach does obtain a meaningful space, and it outperforms strong baselines in text generation benchmarks. The code is available at \url{https://github.com/wenxianxian/demvae}.

Neural models for text generation require a softmax layer with proper token embeddings during the decoding phase. Most existing approaches adopt single point embedding for each token. However, a word may have multiple senses according to different context, some of which might be distinct. In this paper, we propose KerBS, a novel approach for learning better embeddings for text generation. KerBS embodies two advantages: (a) it employs a Bayesian composition of embeddings for words with multiple senses; (b) it is adaptive to semantic variances of words and robust to rare sentence context by imposing learned kernels to capture the closeness of words (senses) in the embedding space. Empirical studies show that KerBS significantly boosts the performance of several text generation tasks.