From Signal to Symphony: Exploring 2D Sequence Representations for Protein Function Prediction

Abstract

Predicting protein function from its primary sequence is a fundamental challenge in computational biology. While deep learning has excelled, the optimal representation of sequence data remains an open question. This study explores protein sonification─the conversion of amino acid sequences into 2D spectrograms─as a representation of this task. To facilitate this investigation, we developed a benchmark data set of 18,000 sequences spanning 12 functionally diverse protein classes. Our systematic evaluation suggests that the structural transformation from a 1D sequence to a 2D spectrogram may be a key contributor to the model's predictive performance. This observation is supported by ablation studies where models using either purely visual or acoustic features from the spectrogram demonstrated effective stand-alone performance, suggesting that the representation itself is a key source of this capability. For instance, a model using a sonification map without explicit biophysical meaning achieved 81.08% accuracy, while our biophysically informed model reached 84.00%, indicating that such domain knowledge may offer a modest performance benefit. When trained from scratch on our data set, our fusion model achieved performance comparable to or slightly exceeding that of standard transformer architectures like ESM-2 and ProtBERT, suggesting its potential for data efficiency in this specific context. The model's potential for generalizability was further supported by its performance on the external CARE enzyme classification benchmark, where it achieved 90.44% accuracy. Finally, as a proof-of-concept, we explore the utility of our encoding to guide a diffusion model in generating novel green fluorescent protein variants, which were assessed for structural viability using computational methods. Our work provides evidence suggesting that the utility of sonification in this context may stem largely from its representational structure, offering a perspective on feature engineering for biological sequences.