AMBER Free Energy Tools: A New Framework for the Design of Optimized Alchemical Transformation Pathways.
AMBER Free Energy Tools: A New Framework for the Design of Optimized Alchemical Transformation Pathways.
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AMBER 免费能源工具：优化炼金转化途径设计的新框架。
DOI：
10.1021/acs.jctc.2c00725
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发表时间：
2023
影响因子：
5.5
通讯作者：
York,DarrinM
中科院分区：
文献类型：
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作者：
Tsai,Hsu-Chun;Lee,Tai-Sung;Ganguly,Abir;Giese,TimothyJ;Ebert,MaximilianCcjc;Labute,Paul;MerzJr,KennethM;York,DarrinM
我们开发了一个框架，用于设计在自由能模拟中使用非线性混合的最优化炼金术转化路径，以及所谓的“软核势”的新的泛函形式。我们描述了该框架在GPU加速的Amber软件套件中的实现和测试。新的优化的炼金术转变路径集成了许多重要的特征，包括(1)使用光滑步骤函数来稳定转变终点附近的行为，(2)一致的功率标度库仑和Lennard-Jones(LJ)相互作用与无单位控制参数以维持静电吸引和交换斥力的平衡，(3)基于LJ接触半径的成对形式的有效相互作用距离与分离位移标度，以及(4)严格的平滑在非键合截止边界的势。新的软核势能形式结合了用于混合特定势能项的平滑转换非线性λ权重，以及灵活的λ调度功能，以实现健壮而稳定的炼金术转化路径。对所得路径进行了验证和测试，结果表明，在所有情况下，所得到的路径在数值稳定性和自由能估计的最小方差方面优于传统方法。本文提出的框架可用于设计新的炼金术增强采样方法，并可用于大型配基数据集的健壮自由能工作流中。
We develop a framework for the design of optimized alchemical transformation pathways in free energy simulations using nonlinear mixing and a new functional form for so-called “softcore” potentials. We describe the implementation and testing of this framework in the GPU-accelerated AMBER software suite. The new optimized alchemical transformation pathways integrate a number of important features, including (1) the use of smoothstep functions to stabilize behavior near the transformation end points, (2) consistent power scaling of Coulomb and Lennard-Jones (LJ) interactions with unitless control parameters to maintain balance of electrostatic attractions and exchange repulsions, (3) pairwise form based on the LJ contact radius for the effective interaction distance with separation-shifted scaling, and (4) rigorous smoothing of the potential at the nonbonded cutoff boundary. The new softcore potential form is combined with smoothly transforming nonlinear λ weights for mixing specific potential energy terms, along with flexible λ-scheduling features, to enable robust and stable alchemical transformation pathways. The resulting pathways are demonstrated and tested, and shown to be superior to the traditional methods in terms of numerical stability and minimal variance of the free energy estimates for all cases considered. The framework presented here can be used to design new alchemical enhanced sampling methods, and leveraged in robust free energy workflows for large ligand data sets.