Automated Force Field Developer and Optimizer Platform: Torsion Reparameterization

General force fields such as General Amber Force Field (GAFF) have been designed for broad applicability and are widely used in protein–ligand binding simulations in structure-based drug discovery. However, the force field parameters are not always transferable across ligand molecules, and custom reparameterization is sometimes necessary for accurate binding free energy simulations. This is especially true for torsion parameters, which are highly dependent on stereoelectronic and steric effects. Here, we report a novel, flexible, and user-friendly computational tool called the Automated Force Field Developer and Optimizer (AFFDO) platform that allows generating accurate, tailored GAFF2 torsion parameters for drug-like molecules. For a given ligand, AFFDO selects the most important torsions, carries out GPU-accelerated density functional theory calculations to collect reference data and fits torsion terms using a fast gradient-based optimizer that leverages automated differentiation. We benchmark AFFDO by parametrizing a series of drug-like molecules and carrying out protein–ligand relative binding free energy (RBFE) simulations. The results show that AFFDO can significantly improve GAFF2 torsion parameters against QM reference data, which in some cases translates into better agreement with experimental RBFE values within a reasonable computational time.通用力场（如通用Amber力场（General Amber Force Field，GAFF））旨在实现广泛适用性，在基于结构的药物发现领域的蛋白质-配体结合模拟中得到广泛应用。然而，力场参数并非总能在不同配体分子间通用，若要获得准确的结合自由能模拟结果，有时需要开展定制化重新参数化工作。对于高度依赖立体电子效应与空间位阻效应的二面角参数而言，这一点尤为突出。本研究报道了一款新颖、灵活且易用的计算工具——自动化力场开发与优化平台（Automated Force Field Developer and Optimizer，AFFDO），可针对类药分子生成精准的定制化GAFF2二面角参数。针对指定配体，AFFDO会筛选出关键二面角，通过图形处理器（Graphics Processing Unit，GPU）加速的密度泛函理论（Density Functional Theory）计算收集参考数据，并借助集成自动微分技术的快速梯度优化器拟合二面角项。本研究通过对一系列类药分子进行参数化，并开展蛋白质-配体相对结合自由能（Relative Binding Free Energy，RBFE）模拟，对AFFDO进行了基准测试。结果表明，相较于量子力学（Quantum Mechanics，QM）参考数据，AFFDO可显著优化GAFF2的二面角参数；在部分场景中，该优化可在合理计算时长内实现与实验RBFE值更高的吻合度。