MOTIVATION: Predicting protein function is a fundamental and challenging task that requires integrating diverse biological data modalities to capture complex functional relationships. Traditional machine learning methods often rely on single modalities or combine only a limited number (typically two), without aligning them in a unified representation, thereby constraining predictive accuracy. Moreover, most existing machine learning approaches are limited to preselected subsets of Gene Ontology (GO) function terms with sufficient annotations, making the prediction of novel function terms a persistent challenge. RESULTS: Here, we present FunBind, a multimodal AI model that jointly learns from five modalities, i.e., protein sequences, textual descriptions, domain annotations, structures, and GO terms, to enhance prediction accuracy and infer previously unseen functions. FunBind operates in two modes: (1) self-supervised pretraining using contrastive learning to align the sequence modality with other heterogeneous modalities in a unified latent space, enabling unsupervised zero-shot function prediction, and (2) supervised fine-tuning of the pretrained model to leverage all non-function modalities for comprehensive and accurate function classification. Our results show that FunBind's zero-shot capabilities allow it to generalize effectively to novel function terms never encountered before, while its joint multimodal fine-tuning strategy outperforms single-modality models and current state-of-the-art deep learning methods in typical function prediction settings. AVAILABILITY: https://github.com/jianlin-cheng/FunBind.

MOTIVATION: Proteins interact with a variety of molecules, including other proteins, DNAs, RNAs, ligands, ions, and lipids. These interactions play a crucial role in cellular communication, metabolic regulation, gene regulation, and structural integrity, making proteins fundamental to nearly all biological functions. Accurately predicting protein interaction (binding) sites is essential for understanding protein interaction and function. RESULTS: In this work, we introduce MPBind, a multitask protein binding site prediction method, which integrates protein language models (PLMs) that can extract structural and functional information from sequences and equivariant graph neural networks (EGNNs) that can effectively capture geometric features of 3D protein structures. Through multitask learning, it can predict binding sites on proteins that interact with five key categories of binding partners: proteins, DNA/RNA, ligands, lipids, and ions. MPBind generalizes across the five molecular classes with state-of-the-art accuracy, achieving AUROC scores of 0.83 and 0.81 for protein-protein and protein-DNA/RNA-binding site prediction, respectively. Moreover, MPBind outperforms both general and task-specific binding site prediction methods, making it a useful, versatile tool for protein binding site prediction. AVAILABILITY AND IMPLEMENTATION: The source code of MPBind is available at the GitHub repository: https://github.com/jianlin-cheng/MPBind.

MOTIVATION: Millions of protein sequences have been generated by numerous genome and transcriptome sequencing projects. However, experimentally determining the function of the proteins is still a time consuming, low-throughput, and expensive process, leading to a large protein sequence-function gap. Therefore, it is important to develop computational methods to accurately predict protein function to fill the gap. Even though many methods have been developed to use protein sequences as input to predict function, much fewer methods leverage protein structures in protein function prediction because there was lack of accurate protein structures for most proteins until recently. RESULTS: We developed TransFun-a method using a transformer-based protein language model and 3D-equivariant graph neural networks to distill information from both protein sequences and structures to predict protein function. It extracts feature embeddings from protein sequences using a pre-trained protein language model (ESM) via transfer learning and combines them with 3D structures of proteins predicted by AlphaFold2 through equivariant graph neural networks. Benchmarked on the CAFA3 test dataset and a new test dataset, TransFun outperforms several state-of-the-art methods, indicating that the language model and 3D-equivariant graph neural networks are effective methods to leverage protein sequences and structures to improve protein function prediction. Combining TransFun predictions and sequence similarity-based predictions can further increase prediction accuracy. AVAILABILITY AND IMPLEMENTATION: The source code of TransFun is available at https://github.com/jianlin-cheng/TransFun.