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Badkundri, R.

Publications and source records attributed to Badkundri, R..

2 recordsLinked to original sources

Language Modeling Materializes a World Model of Protein Biology

Proteins are fundamental to life. The full extent of their biology is beyond our ability to characterize with experimental approaches in the physical laboratory. Accurate digital representations could accelerate the discovery of protein biology through virtual experiments. We propose language modeling to learn unified and general representations that can be scaled to all of protein biology. Building on these representations, we develop a structure prediction model that exceeds the performance of established methods for biomolecular complex prediction across benchmarks, including for the interactions of antibodies with their targets. A simple search procedure yields high experimental success rates for the discovery of proteins with nanomolar binding affinities for both miniproteins and single-chain antibodies, a modality critical for therapeutic design. Study of the concepts in the language models representation space reveals a systematic organization aligned with the reductionist understanding of proteins developed through empirical science. Leveraging this organization, we generate a comprehensive map of protein biology encompassing over 6.8 billion sequences and 1.1 billion predicted structures, identifying connections across known and unknown biology. As a whole, this shows language modeling as a powerful substrate for representing the biology of proteins, operating across scales from the prediction and design of protein interactions at the atomic level, to identifying properties of proteins at different levels of granularity and abstraction, to the scale of mapping connections between proteins across billions of years of evolution.

bioinformatics↗

Simulating 500 million years of evolution with a language model

More than three billion years of evolution have produced an image of biology encoded into the space of natural proteins. Here we show that language models trained on tokens generated by evolution can act as evolutionary simulators to generate functional proteins that are far away from known proteins. We present ESM3, a frontier multimodal generative language model that reasons over the sequence, structure, and function of proteins. ESM3 can follow complex prompts combining its modalities and is highly responsive to biological alignment. We have prompted ESM3 to generate fluorescent proteins with a chain of thought. Among the generations that we synthesized, we found a bright fluorescent protein at far distance (58% identity) from known fluorescent proteins. Similarly distant natural fluorescent proteins are separated by over five hundred million years of evolution.

synthetic biology↗