PaleAle 6.0: Prediction of Protein Relative Solvent Accessibility by Leveraging Pre-Trained Language Models (PLMs).

Predicting the relative solvent accessibility (RSA) of a protein is critical to understanding its 3D structure and biological function. RSA prediction, especially when homology transfer cannot provide information about a protein's structure, is a significant step toward addressing the protein structure prediction challenge. Today, deep learning is arguably the most powerful method for predicting RSA and other structural features of proteins. In particular, recent breakthroughs in deep learning-driven by the integration of natural language processing (NLP) algorithms-have significantly advanced the field of protein research. Inspired by the remarkable success of NLP techniques, this study leverages pre-trained language models (PLMs) to enhance RSA prediction. We present a deep neural network architecture based on a combination of bidirectional recurrent neural networks and convolutional layers that can analyze long-range interactions within protein sequences and predict protein RSA using ESM-2 encoding. The final predictor, PaleAle 6.0, predicts RSA in real values as well as two-state (exposure threshold of 25%) and four-state (exposure thresholds of 4%, 25%, and 50%) discrete classifications. On the 2022 test set dataset, PaleAle 6.0 achieved over 82% accuracy for two-state RSA (RSA_2C) and 59.75% accuracy for four-state RSA (RSA_4C), with a Pearson correlation coefficient (PCC) of 77.88 for real-value RSA prediction. When evaluated on the more challenging 2024 test set, PaleAle 6.0 maintained a strong performance, achieving 79.74% accuracy in the two-state prediction and 55.30% accuracy in the four-state prediction, with a PCC of 73.08 for real-value predictions, outperforming all previously benchmarked predictors.