Hummer Alissa M, Schneider Constantin, Chinery Lewis, Deane Charlotte M
Department of Statistics, University of Oxford, Oxford, UK.
Nat Comput Sci. 2025 Jul 8. doi: 10.1038/s43588-025-00823-8.
Antibody-antigen binding affinity lies at the heart of therapeutic antibody development: efficacy is guided by specific binding and control of affinity. Here we present Graphinity, an equivariant graph neural network architecture built directly from antibody-antigen structures that achieves test Pearson's correlations of up to 0.87 on experimental change in binding affinity (ΔΔG) prediction. However, our model, like previous methods, appears to be overtraining on the few hundred experimental data points available and performance is not robust to train-test cut-offs. To investigate the amount and type of data required to generalizably predict ΔΔG, we built synthetic datasets of nearly 1 million FoldX-generated and >20,000 Rosetta Flex ddG-generated ΔΔG values. Our results indicate that there are currently insufficient experimental data to accurately and robustly predict ΔΔG, with orders of magnitude more likely needed. Dataset size is not the only consideration; diversity is also an important factor for model predictiveness. These findings provide a lower bound on data requirements to inform future method development and data collection efforts.
抗体-抗原结合亲和力是治疗性抗体开发的核心:疗效由特异性结合和亲和力控制所引导。在此,我们展示了Graphinity,一种直接基于抗体-抗原结构构建的等变图神经网络架构,在结合亲和力实验变化(ΔΔG)预测方面,其测试皮尔逊相关系数高达0.87。然而,我们的模型与先前方法一样,似乎在可用的几百个实验数据点上过度训练,并且性能对训练-测试分割并不稳健。为了研究可泛化预测ΔΔG所需的数据量和类型,我们构建了近100万个由FoldX生成的以及超过20000个由Rosetta Flex ddG生成的ΔΔG值的合成数据集。我们的结果表明,目前尚无足够的实验数据来准确且稳健地预测ΔΔG,可能需要数量级更多的数据。数据集大小并非唯一考量因素;多样性也是影响模型预测能力的重要因素。这些发现为数据需求提供了下限,以指导未来的方法开发和数据收集工作。