Computational biology and bioinformatics provide vast data gold-mines from protein sequences, ideal for Language Models taken from NLP. These LMs reach for new prediction frontiers at low inference costs. Here, we trained two auto-regressive models (Transformer-XL, XLNet) and four auto-encoder models (BERT, Albert, Electra, T5) on data from UniRef and BFD containing up to 393 billion amino acids. The LMs were trained on the Summit supercomputer using 5616 GPUs and TPU Pod up-to 1024 cores. Dimensionality reduction revealed that the raw protein LM-embeddings from unlabeled data captured some biophysical features of protein sequences. We validated the advantage of using the embeddings as exclusive input for several subsequent tasks. The first was a per-residue prediction of protein secondary structure (3-state accuracy Q3=81%-87%); the second were per-protein predictions of protein sub-cellular localization (ten-state accuracy: Q10=81%) and membrane vs. water-soluble (2-state accuracy Q2=91%). For the per-residue predictions the transfer of the most informative embeddings (ProtT5) for the first time outperformed the state-of-the-art without using evolutionary information thereby bypassing expensive database searches. Taken together, the results implied that protein LMs learned some of the grammar of the language of life. To facilitate future work, we released our models at https://github.com/agemagician/ProtTrans.

Motivation: Natural Language Processing (NLP) continues improving substantially through auto-regressive (AR) and auto-encoding (AE) Language Models (LMs). These LMs require expensive computing resources for self-supervised or un-supervised learning from huge unlabelled text corpora. The information learned is transferred through so-called embeddings to downstream prediction tasks. Computational biology and bioinformatics provide vast gold-mines of structured and sequentially ordered text data leading to extraordinarily successful protein sequence LMs that promise new frontiers for generative and predictive tasks at low inference cost. As recent NLP advances link corpus size to model size and accuracy, we addressed two questions: (1) To which extent can High-Performance Computing (HPC) up-scale protein LMs to larger databases and larger models? (2) To which extent can LMs extract features from single proteins to get closer to the performance of methods using evolutionary information? Methodology: Here, we trained two auto-regressive language models (Transformer-XL and XLNet) and two auto-encoder models (BERT and Albert) on 80 billion amino acids from 200 million protein sequences (UniRef100) and one language model (Transformer-XL) on 393 billion amino acids from 2.1 billion protein sequences taken from the Big Fat Database (BFD), today's largest set of protein sequences (corresponding to 22- and 112-times, respectively of the entire English Wikipedia). The LMs were trained on the Summit supercomputer, using 936 nodes with 6 GPUs each (in total 5616 GPUs) and one TPU Pod, using V3-512 cores. Results: We validated the feasibility of training big LMs on proteins and the advantage of up-scaling LMs to larger models supported by more data. The latter was assessed by predicting secondary structure in three- and eight-states (Q3=75-83, Q8=63-72), localization for 10 cellular compartments (Q10=74) and whether a protein is membrane-bound or water-soluble (Q2=89). Dimensionality reduction revealed that the LM-embeddings from unlabelled data (only protein sequences) captured important biophysical properties of the protein alphabet, namely the amino acids, and their well orchestrated interplay in governing the shape of proteins. In the analogy of NLP, this implied having learned some of the grammar of the language of life realized in protein sequences. The successful up-scaling of protein LMs through HPC slightly reduced the gap between models trained on evolutionary information and LMs. Additionally, our results highlighted the importance of bi-directionality when processing proteins as the uni-directional TransformerXL was outperformed by its bi-directional counterparts. Availability ProtTrans: <a href="https://github.com/agemagician/ProtTrans">https://github.com/agemagician/ProtTrans</a>

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