Zhang Yichuan, Qin Yongfang, Pourmirzaei Mahdi, Shao Qing, Wang Duolin, Xu Dong
Department of Electrical Engineering and Computer Science and Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
Chemical & Materials Engineering, University of Kentucky, Lexington, KY, USA.
Methods Mol Biol. 2025;2941:31-58. doi: 10.1007/978-1-0716-4623-6_2.
Proteins are crucial in a wide range of biological and engineering processes. Large protein language models (PLMs) can significantly advance our understanding and engineering of proteins. However, the effectiveness of PLMs in prediction and design is largely based on the representations derived from protein sequences. Without incorporating the three-dimensional (3D) structures of proteins, PLMs would overlook crucial aspects of how proteins interact with other molecules, thereby limiting their predictive accuracy. To address this issue, we present S-PLM, a 3D structure-aware PLM, that employs multi-view contrastive learning to align protein sequences with their 3D structures in a unified latent space. Previously, we utilized a contact map-based approach to encode structural information, applying the Swin-Transformer to contact maps derived from AlphaFold-predicted protein structures. This work introduces a new approach that leverages a geometric vector perceptron (GVP) model to process 3D coordinates and obtain structural embeddings. We focus on the application of structure-aware models for protein-related tasks by utilizing efficient fine-tuning methods to achieve optimal performance without significant computational costs. Our results show that S-PLM outperforms sequence-only PLMs across all protein clustering and classification tasks, achieving performance on par with state-of-the-art methods that require both sequence and structure inputs. S-PLM and its tuning tools are available at https://github.com/duolinwang/S-PLM/ .
蛋白质在广泛的生物和工程过程中至关重要。大型蛋白质语言模型(PLM)可以显著推进我们对蛋白质的理解和工程应用。然而,PLM在预测和设计方面的有效性很大程度上基于从蛋白质序列中得出的表示。如果不纳入蛋白质的三维(3D)结构,PLM将忽略蛋白质与其他分子相互作用的关键方面,从而限制其预测准确性。为了解决这个问题,我们提出了S-PLM,一种3D结构感知的PLM,它采用多视图对比学习在统一的潜在空间中将蛋白质序列与其3D结构对齐。此前,我们利用基于接触图的方法来编码结构信息,将Swin-Transformer应用于从AlphaFold预测的蛋白质结构中得出的接触图。这项工作引入了一种新方法,利用几何向量感知器(GVP)模型来处理3D坐标并获得结构嵌入。我们通过利用高效的微调方法在不产生显著计算成本的情况下实现最佳性能,专注于结构感知模型在蛋白质相关任务中的应用。我们的结果表明,在所有蛋白质聚类和分类任务中,S-PLM的性能优于仅基于序列的PLM,达到了与需要序列和结构输入的最先进方法相当的性能。S-PLM及其微调工具可在https://github.com/duolinwang/S-PLM/获取。