Papers for
computational drug developers
Papers whose findings have a practical use for this group, as judged from the abstract. Open a paper to read what it means in practice.
RNA design method improves 3D folding using geometry and latent diffusion
GOLD: Geometric Optimized Latent Diffusion for Structure-Aware RNA Inverse Folding
Abstract: Designing RNA sequences that fold into specific 3D structures is a fundamental challenge in therapeutics. Current RNA inverse folding methods typically condition on 3D backbone coordinates but the generation is limited to 1D discrete sequences. This ignores the continuous side-chain orientations, which are essential for overall structural stability. To address this issue, we explicitly introduce side-chain geometry into the RNA generative process. Unlike co-design frameworks that diffuse across separate raw spaces, we propose Geometric Optimized Latent Diffusion (\textbf{GOLD}), which project sequence and structure into a unified latent manifold. GOLD employs a novel GeoVAE to elegantly integrate discrete RNA sequences with continuous side-chain angles. By mapping these modalities into a single, smooth latent manifold, GOLD naturally facilitates a synergistic co-diffusion process. To enhance structural validity, we further introduce a training-free, gradient-guided sampling mechanism. By decoding the generated sequence probabilities and side-chain geometries into structures during the sampling process, we compute analytical gradients from physical constraints. This dynamic feedback actively guides the generated sequence to a physically stable state. Extensive experiments validate the superiority of GOLD, achieving state-of-the-art performance across sequence recovery, secondary structure validity, and 3D foldability metrics. Our code and data are publicly available at https://github.com/darkflash03/GOLD.
Protein mutation analysis improved by separating structure and properties
RipplePLM: Structural and Property Decoupling for Protein Mutation Effect Generation
Abstract: Protein mutation effect generation asks a model to describe the functional consequence of a point mutation in natural language. Existing protein-to-text systems typically encode mutation information into undifferentiated representations, overlooking the organization of mutation-induced evidence across structural and biochemical factors. We propose RipplePLM, a mutation-aware generation framework centered on Direct-Distal Cross-Attention (DDCA). By constructing a residue-level Mutation Perturbation Field from pre-trained protein language models, DDCA leverages predicted contact maps to organize mutation representations into two pathways: the mutation site's immediate contact neighborhood and its multi-hop distal context. To complement this structural decomposition, we further introduce the Property Latent Chain (PLChain), which injects expert-guided supervision of biochemical property changes (e.g., thermostability and optimal pH) into the LLM hidden-state pathway through latent property tokens. On MutaDescribe, RipplePLM improves over mutation-specific baselines on temporal and structural splits; under a matched-backbone comparison, average structural-split ROUGE-L increases from {22.23} to {35.65}. Expert evaluation further shows a higher proportion of biologically accurate or relevant descriptions than the mutation-specific baseline. Additional ablations, representation diagnostics, and low-$N$ fitness regression experiments further support the effectiveness of the learned mutation-aware representations. Code: https://github.com/Lyu6PosHao/RipplePLM.