Generative Enzyme Design Guided by Functionally Important Sites and Small-Molecule Substrates

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.

SurfPro: Functional Protein Design Based on Continuous Surface

How can we design proteins with desired functions? We are motivated by a chemical intuition that both geometric structure and biochemical properties are critical to a protein's function. In this paper, we propose SurfPro, a new method to generate functional proteins given a desired surface and its associated biochemical properties. SurfPro comprises a hierarchical encoder that progressively models the geometric shape and biochemical features of a protein surface, and an autoregressive decoder to produce an amino acid sequence. We evaluate SurfPro on a standard inverse folding benchmark CATH 4.2 and two functional protein design tasks: protein binder design and enzyme design. Our SurfPro consistently surpasses previous state-of-the-art inverse folding methods, achieving a recovery rate of 57.78% on CATH 4.2 and higher success rates in terms of protein-protein binding and enzyme-substrate interaction scores.

Hire a Linguist!: Learning Endangered Languages with In-Context Linguistic Descriptions

How can large language models (LLMs) process and translate endangered languages? Many languages lack a large corpus to train a decent LLM; therefore existing LLMs rarely perform well in unseen, endangered languages. On the contrary, we observe that 2000 endangered languages, though without a large corpus, have a grammar book or a dictionary. We propose LINGOLLM, a training-free approach to enable an LLM to process unseen languages that hardly occur in its pre-training. Our key insight is to demonstrate linguistic knowledge of an unseen language in an LLM's prompt, including a dictionary, a grammar book, and morphologically analyzed input text. We implement LINGOLLM on top of two models, GPT-4 and Mixtral, and evaluate their performance on 5 tasks across 8 endangered or low-resource languages. Our results show that LINGOLLM elevates translation capability from GPT-4's 0 to 10.5 BLEU for 10 language directions. Our findings demonstrate the tremendous value of linguistic knowledge in the age of LLMs for endangered languages. Our data, code, and model generations can be found at https://github.com/LLiLab/llm4endangeredlang.

Functional Geometry Guided Protein Sequence and Backbone Structure Co-Design

Proteins are macromolecules responsible for essential functions in almost all living organisms. Designing reasonable proteins with desired functions is crucial. A protein's sequence and structure are strongly correlated and they together determine its function. In this paper, we propose NAEPro, a model to jointly design Protein sequence and structure based on automatically detected functional sites. NAEPro is powered by an interleaving network of attention and equivariant layers, which can capture global correlation in a whole sequence and local influence from nearest amino acids in three dimensional (3D) space. Such an architecture facilitates effective yet economic message passing at two levels. We evaluate our model and several strong baselines on two protein datasets, $\beta$-lactamase and myoglobin. Experimental results show that our model consistently achieves the highest amino acid recovery rate, TM-score, and the lowest RMSD among all competitors. These findings prove the capability of our model to design protein sequences and structures that closely resemble their natural counterparts. Furthermore, in-depth analysis further confirms our model's ability to generate highly effective proteins capable of binding to their target metallocofactors. We provide code, data and models in Github.

Joint Design of Protein Sequence and Structure based on Motifs

Designing novel proteins with desired functions is crucial in biology and chemistry. However, most existing work focus on protein sequence design, leaving protein sequence and structure co-design underexplored. In this paper, we propose GeoPro, a method to design protein backbone structure and sequence jointly. Our motivation is that protein sequence and its backbone structure constrain each other, and thus joint design of both can not only avoid nonfolding and misfolding but also produce more diverse candidates with desired functions. To this end, GeoPro is powered by an equivariant encoder for three-dimensional (3D) backbone structure and a protein sequence decoder guided by 3D geometry. Experimental results on two biologically significant metalloprotein datasets, including $\beta$-lactamases and myoglobins, show that our proposed GeoPro outperforms several strong baselines on most metrics. Remarkably, our method discovers novel $\beta$-lactamases and myoglobins which are not present in protein data bank (PDB) and UniProt. These proteins exhibit stable folding and active site environments reminiscent of those of natural proteins, demonstrating their excellent potential to be biologically functional.

INSTRUCTSCORE: Towards Explainable Text Generation Evaluation with Automatic Feedback

The field of automatic evaluation of text generation made tremendous progress in the last few years. In particular, since the advent of neural metrics, like COMET, BLEURT, and SEScore2, the newest generation of metrics show a high correlation with human judgment. Unfortunately, quality scores generated with neural metrics are not interpretable, and it is unclear which part of the generation output is criticized by the metrics. To address this limitation, we present INSTRUCTSCORE, an open-source, explainable evaluation metric for text generation. By harnessing both explicit human instruction and the implicit knowledge of GPT4, we fine-tune a LLAMA model to create an evaluative metric that can produce a diagnostic report aligned with human judgment. We evaluate INSTRUCTSCORE on the WMT22 Zh-En translation task, where our 7B model surpasses other LLM-based baselines, including those based on 175B GPT3. Impressively, our INSTRUCTSCORE, even without direct supervision from human-rated data, achieves performance levels on par with state-of-the-art metrics like COMET22, which was fine-tuned on human ratings.

Importance Weighted Expectation-Maximization for Protein Sequence Design

Designing protein sequences with desired biological function is crucial in biology and chemistry. Recent machine learning methods use a surrogate sequence-function model to replace the expensive wet-lab validation. How can we efficiently generate diverse and novel protein sequences with high fitness? In this paper, we propose IsEM-Pro, an approach to generate protein sequences towards a given fitness criterion. At its core, IsEM-Pro is a latent generative model, augmented by combinatorial structure features from a separately learned Markov random fields (MRFs). We develop an Monte Carlo Expectation-Maximization method (MCEM) to learn the model. During inference, sampling from its latent space enhances diversity while its MRFs features guide the exploration in high fitness regions. Experiments on eight protein sequence design tasks show that our IsEM-Pro outperforms the previous best methods by at least 55% on average fitness score and generates more diverse and novel protein sequences.

MTG: A Benchmarking Suite for Multilingual Text Generation

We introduce MTG, a new benchmark suite for training and evaluating multilingual text generation. It is the first and largest text generation benchmark with 120k human-annotated multi-way parallel data for three tasks (story generation, question generation, and title generation) across four languages (English, German, French, and Spanish). Based on it, we set various evaluation scenarios and make a deep analysis of several popular multilingual generation models from different aspects. Our benchmark suite will encourage the multilingualism for text generation community with more human-annotated parallel data and more diverse generation scenarios.

Triangular Bidword Generation for Sponsored Search Auction

Sponsored search auction is a crucial component of modern search engines. It requires a set of candidate bidwords that advertisers can place bids on. Existing methods generate bidwords from search queries or advertisement content. However, they suffer from the data noise in <query, bidword> and <advertisement, bidword> pairs. In this paper, we propose a triangular bidword generation model (TRIDENT), which takes the high-quality data of paired <query, advertisement> as a supervision signal to indirectly guide the bidword generation process. Our proposed model is simple yet effective: by using bidword as the bridge between search query and advertisement, the generation of search query, advertisement and bidword can be jointly learned in the triangular training framework. This alleviates the problem that the training data of bidword may be noisy. Experimental results, including automatic and human evaluations, show that our proposed TRIDENT can generate relevant and diverse bidwords for both search queries and advertisements. Our evaluation on online real data validates the effectiveness of the TRIDENT's generated bidwords for product search.

Improving Coreference Resolution by Leveraging Entity-Centric Features with Graph Neural Networks and Second-order Inference

One of the major challenges in coreference resolution is how to make use of entity-level features defined over clusters of mentions rather than mention pairs. However, coreferent mentions usually spread far apart in an entire text, which makes it extremely difficult to incorporate entity-level features. We propose a graph neural network-based coreference resolution method that can capture the entity-centric information by encouraging the sharing of features across all mentions that probably refer to the same real-world entity. Mentions are linked to each other via the edges modeling how likely two linked mentions point to the same entity. Modeling by such graphs, the features between mentions can be shared by message passing operations in an entity-centric manner. A global inference algorithm up to second-order features is also presented to optimally cluster mentions into consistent groups. Experimental results show our graph neural network-based method combing with the second-order decoding algorithm (named GNNCR) achieved close to state-of-the-art performance on the English CoNLL-2012 Shared Task dataset.