Lambda-ABF：简化、可移植、精确且高性价比的炼金自由能计算
Lambda-ABF: Simplified, Portable, Accurate and Cost-effective Alchemical Free Energy Computations
AI总结：
提出基于多重行走者ABF与强阻尼Langevin $λ$-动力学的炼金自由能计算方法，无需手动优化且计算成本大幅降低，在NAMD和Tinker-HP中实现并验证其高效精确。
摘要：
我们引入了一种高效且鲁棒的方法来计算炼金自由能差异，该方法源于多重行走者自适应偏置力（ABF）与强阻尼Langevin $λ$-动力学的结合应用。无偏的炼金自由能面可通过热力学积分（TI）自然恢复。无需对 $λ$ 调度进行手动优化，因为 $λ$ 变量的采样是连续的，并收敛于均匀分布。与固定 $λ$ 方法（如标准TI或自由能微扰（FEP））相比，$λ$ 的自由扩散改善了正交弛豫。此外，多重行走者策略以极少的用户输入和可忽略的计算开销，提供了一种通用的正交空间覆盖方式。在实际应用中，该方法不假设炼金度与笛卡尔自由度之间存在绝热解耦，从而确保在广泛的数值参数范围内获得无偏估计。我们在生产级分子动力学引擎NAMD和Tinker-HP中，通过与Colvars开源库耦合，展示了该方法的两种高性能实现。这些接口实现了这些软件包丰富功能集的结合。我们在多个实际案例中证明了该方法的正确性和效率：从溶剂化自由能到配体-受体结合（使用最近提出的结合约束方案），涵盖了固定电荷和极化模型。我们发现，在选定精度下，与最先进的固定 $λ$ 方法相比，计算成本大幅降低，且对于最复杂的系统，恢复的结果与实验值的误差在1~kcal/mol以内。该实现已公开提供，当前炼金方法从业者可直接使用。
英文摘要：
We introduce an efficient and robust method to compute alchemical free energy differences, resulting from the application of multiple walker Adaptive Biasing Force (ABF) in conjunction with strongly damped Langevin $λ$-dynamics. Unbiased alchemical free energy surfaces are naturally recovered by Thermodynamic Integration (TI). No manual optimization of the $λ$ schedule is required as the sampling of the $λ$ variable is continuous and converges towards a uniform distribution. Free diffusion of $λ$ improves orthogonal relaxation compared to fixed $λ$ methods such as standard TI or Free Energy Perturbation (FEP). Furthermore, the multiple walker strategy provides coverage of orthogonal space in a generic way with minimal user input and negligible computational overhead. Of practical importance, no adiabatic decoupling between the alchemical and Cartesian degrees of freedom is assumed, ensuring unbiased estimates for a wide envelope of numerical parameters. We present two high-performance implementations of the method in production molecular dynamics engines, namely NAMD and Tinker-HP, through coupling with the Colvars open source library. These interfaces enable the combination of the rich feature sets of those packages. We demonstrate the correctness and efficiency of the approach on several real-world cases: from solvation free energies up to ligand-receptor binding (using a recently proposed binding restraint scheme) with both fixed-charge and polarizable models. We find that, for a chosen accuracy, the computational cost is strongly reduced compared to state-of-the-art fixed-lambda methods and that results within 1~kcal/mol of experimental value are recovered for the most complex system. The implementation is publicly available and readily usable by practitioners of current alchemical methods.
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