Linker-Tuning: Optimizing Continuous Prompts for Heterodimeric Protein Prediction

Abstract: Predicting the structure of interacting chains is crucial for understanding biological systems and developing new drugs. Large-scale pre-trained Protein LLMs (PLMs), such as ESM2, have shown impressive abilities in extracting biologically meaningful representations for protein structure prediction. In this paper, we show that ESMFold, which has been successful in computing accurate atomic structures for single-chain proteins, can be adapted to predict the heterodimer structures in a lightweight manner. We propose Linker-tuning, which learns a continuous prompt to connect the two chains in a dimer before running it as a single sequence in ESMFold. Experiment results show that our method successfully predicts 56.98% of interfaces on the i.i.d. heterodimer test set, with an absolute improvement of +12.79% over the ESMFold-Linker baseline. Furthermore, our model can generalize well to the out-of-distribution (OOD) test set HeteroTest2 and two antibody test sets Fab and Fv while being $9\times$ faster than AF-Multimer.