Beyond RNA Structure Alone: Complex-Aware Fusion for Tertiary Structure-based RNA Design

Zixun Zhang, Jiayou Zheng, Yuzhe Zhou, Sheng Wang, Shuguang Cui, Zhen Li

Keywords: tertiary structure-based RNA design, complex-aware attention, distance-aware filtering

TL;DR: In this paper, we propose the Complex-Aware tertiary structure-based RNA Design model, CARD, that integrates complex-level information to enhance tertiary structure-based RNA sequence design.

Abstract: Tertiary structure-based RNA design plays a crucial role in synthetic biology and therapeutics. While existing methods have explored structure-to-sequence mappings, they focus solely on RNA structures and overlook the role of complex-level information, which is crucial for effective RNA design. To address this limitation, we propose the Complex-Aware tertiary structure-based RNA Design model, CARD, that integrates complex-level information to enhance tertiary structure-based RNA sequence design. To be specific, our method incorporates protein features extracted by protein language model (e.g., ESM-2), enabling the design model to generate more accurate and complex relevant sequences. Considering the biological complexity of protein-RNA interactions, we introduce a distance-aware filtering for local features from protein representation. Furthermore, we design a high-affinity design framework that combines our CARD with an affinity evaluation model. In this framework, candidate RNA sequences are generated and rigorously screened based on affinity and structural alignment to produce high-affinity RNA sequences. Extensive experiments demonstrate the effectiveness of our method with an improvement of 7.3% compared with base model without our complex-aware feature integration. A concrete case study for 2LBS further validates the superiority of our CARD.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

Submission Number: 1844