AMBER Drug Discovery Boost Tools: Automated Workflow for Production Free-Energy Simulation Setup and Analysis (ProFESSA),Journal of Chemical Information and Modeling

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AMBER Drug Discovery Boost Tools: Automated Workflow for Production Free-Energy Simulation Setup and Analysis (ProFESSA)
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-11-30 , DOI: 10.1021/acs.jcim.2c00879
Abir Ganguly ₁ , Hsu-Chun Tsai ₁ , Mario Fernández-Pendás _{1,

2} , Tai-Sung Lee ₁ , Timothy J Giese ₁ , Darrin M York ₁

Affiliation

We report an automated workflow for production free-energy simulation setup and analysis (ProFESSA) using the GPU-accelerated AMBER free-energy engine with enhanced sampling features and analysis tools, part of the AMBER Drug Discovery Boost package that has been integrated into the AMBER22 release. The workflow establishes a flexible, end-to-end pipeline for performing alchemical free-energy simulations that brings to bear technologies, including new enhanced sampling features and analysis tools, to practical drug discovery problems. ProFESSA provides the user with top-level control of large sets of free-energy calculations and offers access to the following key functionalities: (1) automated setup of file infrastructure; (2) enhanced conformational and alchemical sampling with the ACES method; and (3) network-wide free-energy analysis with the optional imposition of cycle closure and experimental constraints. The workflow is applied to perform absolute and relative solvation free-energy and relative ligand–protein binding free-energy calculations using different atom-mapping procedures. Results demonstrate that the workflow is internally consistent and highly robust. Further, the application of a new network-wide Lagrange multiplier constraint analysis that imposes key experimental constraints substantially improves binding free-energy predictions.

中文翻译：

AMBER 药物发现促进工具：用于生产自由能模拟设置和分析的自动化工作流程 (ProFESSA)

我们报告了一种用于生产自由能模拟设置和分析 (ProFESSA) 的自动化工作流程，该工作流程使用 GPU 加速的 AMBER 自由能引擎，具有增强的采样功能和分析工具，是已集成到 AMBER22 中的 AMBER Drug Discovery Boost 包的一部分发布。该工作流程建立了一个灵活的端到端管道，用于执行炼金术自由能模拟，为实际的药物发现问题带来技术，包括新的增强采样功能和分析工具。 ProFESSA 为用户提供对大量自由能计算的顶层控制，并提供对以下关键功能的访问：(1) 文件基础设施的自动设置； (2) 使用 ACES 方法增强构象和炼金采样； (3) 网络范围内的自由能分析，可选择施加循环闭合和实验约束。该工作流程用于使用不同的原子映射程序执行绝对和相对溶剂化自由能以及相对配体-蛋白质结合自由能计算。结果表明，工作流程内部一致且高度稳健。此外，应用新的全网络拉格朗日乘子约束分析，施加关键的实验约束，大大改善了结合自由能预测。

更新日期：2022-11-30

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