CrossLLM-Mamba: Multimodal State Space Fusion of LLMs for RNA Interaction Prediction

The accurate prediction of protein-RNA binding affinity remains an unsolved problem in structural biology, limiting opportunities in understanding gene regulation and designing RNA-targeting therapeutics. A central obstacle is the structural flexibility of RNA, as, unlike proteins, RNA molecules exist as dynamic conformational ensembles. Thus, committing to a single predicted structure discards information relevant to binding. Here, we show that this obstacle can be addressed by extracting pre-structural embeddings, which are intermediate representations from a biomolecular foundation model captured before the structure decoding step. Pre-structural embeddings implicitly encode conformational ensemble information without requiring predicted structures. We build ZeroFold, a transformer-based model that combines pre-structural embeddings from Boltz-2 for both protein and RNA molecules through a cross-modal attention mechanism to predict binding affinity directly from sequence. To support training and evaluation, we construct PRADB, a curated dataset of 2,621 unique protein-RNA pairs with experimentally measured affinities drawn from four complementary databases. On a held-out test set constructed with 40% sequence identity thresholds, ZeroFold achieves a Spearman correlation of 0.65, a value approaching the ceiling imposed by experimental measurement noise. Under progressively fairer evaluation conditions that control for training-set overlap, ZeroFold compares favourably with respect to leading structure-based and leading sequence-based predictors, with the performance gap widening as sequence similarity to competitor training data is reduced. These results illustrate how pre-structural embeddings offer a representation strategy for flexible biomolecules, opening a route to affinity prediction for protein-RNA pairs for which no structural data exist.

Protein-protein interactions (PPIs) are essential for many biological processes. However, existing PPI prediction approaches suffer from two major limitations: they overlook the hierarchical organization of proteins, particularly meso-scale motifs that critically regulate PPIs, and fail to effectively integrate sequence, structure, and function modalities. To address these limitations, we propose MMM-PPI, a Hierarchical Motif-based Multi-Modal protein Encoder for PPI Prediction that constructs PPI embeddings in a bottom-up multi-modal manner across three scales. At the micro-scale, we encode three modal residue features; at the meso-scale, a novel multimodal motif encoder aggregates residues into spatially-informed motif embeddings; at the macro-scale, a multimodal protein encoder integrates motifs into protein embeddings by jointly modeling motif importance and inter-modal correlations. The pre-trained encoder can be used off-the-shelf for large-scale PPI prediction. Extensive experiments on multiple PPI datasets show that MMM-PPI outperforms state-of-the-art multi-label PPI prediction models, particularly under challenging data partitions and limited data scenarios. Codes are in https://github.com/yzf-code/MMM-PPI.

The design of RNA molecules that interact with specific proteins is a critical challenge in experimental and computational biology. Despite recent progress in natural language modeling and deep learning-based protein design, there remains significant room to improve the frequency of successful interactions and the authenticity of generated sequences for functional applications. In this work, we frame conditional RNA sequence generation as a multi-stage alignment problem, introducing Moirain: a suite of models optimized via multimodal supervised fine-tuning (SFT) and Direct Preference Optimization (DPO). Our approach begins with large-scale pretraining on diverse RNA corpora to capture the fundamental grammars of sequence plausibility. To achieve target-specific generation, we employ a multimodal SFT architecture that conditions RNA synthesis on protein structural and sequential features. Finally, we leverage DPO to refine the model using synthetic interaction data: taking advantage of DPO's unique ability to navigate non-aligned preference spaces, we improve functional fitness without collapsing the learned natural distribution. Extensive evaluation of the Moirain series (Moirain-Base, -Multi, and -DPO) demonstrates that our framework consistently produces novel, diverse, and biologically plausible RNA sequences with superior binding affinities compared to existing baselines.