Accelerating Protein Docking in ZDOCK Using an Advanced 3D Convolution Library

Computational prediction of the 3D structures of molecular interactions is a challenging area, often requiring significant computational resources to produce structural predictions with atomic-level accuracy. This can be particularly burdensome when modeling large sets of interactions, macromolecular assemblies, or interactions between flexible proteins. We previously developed a protein docking program, ZDOCK, which uses a fast Fourier transform to perform a 3D search of the spatial degrees of freedom between two molecules. By utilizing a pairwise statistical potential in the ZDOCK scoring function, there were notable gains in docking accuracy over previous versions, but this improvement in accuracy came at a substantial computational cost. In this study, we incorporated a recently developed 3D convolution library into ZDOCK, and additionally modified ZDOCK to dynamically orient the input proteins for more efficient convolution. These modifications resulted in an average of over 8.5-fold improvement in running time when tested on 176 cases in a newly released protein docking benchmark, as well as substantially less memory usage, with no loss in docking accuracy. We also applied these improvements to a previous version of ZDOCK that uses a simpler non-pairwise atomic potential, yielding an average speed improvement of over 5-fold on the docking benchmark, while maintaining predictive success. This permits the utilization of ZDOCK for more intensive tasks such as docking flexible molecules and modeling of interactomes, and can be run more readily by those with limited computational resources.分子相互作用三维结构的计算预测是极具挑战性的研究方向，通常需要依托大量计算资源，方可获得具备原子级精度的结构预测结果。在对大规模相互作用集、大分子组装体或柔性蛋白质间的相互作用进行建模时，该任务的计算负担尤为沉重。我们此前开发了蛋白质对接程序ZDOCK，该程序通过快速傅里叶变换（Fast Fourier Transform）对两个分子间的空间自由度开展三维搜索。通过在ZDOCK的打分函数中引入成对统计势能，该程序的对接精度相较旧版得到了显著提升，但精度的优化伴随着高昂的计算成本。本研究中，我们将新近开发的三维卷积库集成至ZDOCK中，并对ZDOCK进行了优化，使其能够对输入蛋白质进行动态定向，以实现更高效的卷积运算。在最新发布的蛋白质对接基准测试集的176个样本中开展测试时，上述优化使程序运行时间平均提升8.5倍以上，同时内存占用大幅降低，且对接精度未受任何影响。我们还将这些优化应用于采用更简单非成对原子势能的旧版ZDOCK，在该对接基准测试集上实现了平均5倍以上的速度提升，且保留了原有的预测性能。这使得ZDOCK能够适用于柔性分子对接、相互作用组建模等更高计算量的任务，同时也让计算资源有限的研究者能够更便捷地运行该程序。