Multi-objective Genetic Programming with Multi-view Multi-level Feature for Enhanced Protein Secondary Structure Prediction

Intrinsically disordered regions of proteins play a crucial role in cell signaling and drug discovery. However, their high structural flexibility makes accurate residue-level prediction challenging. Existing methods often rely on single-view representations or rigid manual fusion strategies, which fail to effectively balance the complex interplay between local amino acid preferences and long-range sequence patterns. To address these limitations, we propose D2MOE, a Dual-View Multiscale Features and Multi-objective Evolutionary Algorithm, which consists of two stages. First, a dual-view multiscale feature extraction method is introduced. This method integrates evolutionary views with deep semantic views and employs multiscale extractors to capture structural information across diverse receptive fields. Second, a multi-objective evolutionary algorithm is designed to adaptively discover optimal fusion architectures. By co-evolving discrete feature selection and continuous fusion weights, the algorithm adaptively explores optimal cross-feature architectures to enhance predictive accuracy while maintaining model compactness. Experimental results across three benchmark datasets demonstrate that D2MOE consistently outperforms state-of-the-art methods. D2MOE combines the feature extraction capabilities of deep learning with the global search advantages of evolutionary algorithms, enabling efficient feature integration without manual design, and providing a robust computational tool for protein disorder prediction.

Accurate protein structure prediction is fundamental to structural biology because protein structure underlies molecular function and provides a basis for mechanistic interpretation. Recent advances in deep learning have transformed the field from multiple sequence alignment (MSA)-driven monomer folding into broader frameworks capable of modeling protein complexes and increasingly heterogeneous molecular systems. Existing reviews have summarized this progress from the perspectives of representative models, application domains, and protein design. Building on these efforts, this review focuses on the methodological evolution of the field itself. It examines recent developments through three closely related dimensions: representations and data, architectures and learning strategies, and confidence and evaluation. Within this perspective, the field is organized into four methodological phases and three cross-cutting transitions: from explicit evolutionary coupling features and early contact prediction to learned sequence representations in AlphaFold2, RoseTTAFold, and ESMFold; from protein-only monomer folding to increasingly integrated modeling of heterogeneous molecular systems in AlphaFold-Multimer, RoseTTAFoldNA, and AlphaFold3; and, more recently, from prediction-oriented structure inference to design-oriented generative modeling in RFdiffusion and related frameworks. This framework provides a clearer understanding of how methodological shifts have shaped the capabilities, limitations, and practical roles of recent models.

Protein optimization remains a longstanding goal in life sciences. Existing machine learning-assisted directed evolution (MLDE) methods primarily rely on sequence-only features, overlooking the critical spatial constraints and co-evolutionary interactions encoded in protein structures. However, directly integrating structural information remains challenging due to the scarcity of reliable mutant structures. To address these issues, we propose StructEvo, a novel structure-aware reinforcement learning framework for protein directed evolution. StructEvo employs a delta-structure fusion encoder to approximate mutant structure features via feature differences, enabling dynamic incorporation of spatial knowledge. The vast mutation space is then decomposed into manageable subspaces through a structure-aligned hierarchical action network, while a geometric constraint further stabilizes delta feature learning. Our approach outperforms prior state-of-the-art methods by 9.2% and 16.3% on two challenging optimization benchmarks, and further identifies an experimentally validated epistasis pattern in GFP, highlighting the importance of structural guidance for effective protein directed evolution.