Binding Kinetics Toolkit for Analyzing Transient Molecular Conformations and Computing Free Energy Landscapes.
Binding Kinetics Toolkit for Analyzing Transient Molecular Conformations and Computing Free Energy Landscapes.
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DOI：
10.1021/acs.jpca.2c05499
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发表时间：
2022-11-24
影响因子：
2.9
通讯作者：
Chang, Chia-en A.
中科院分区：
文献类型：
--
作者：
Ruzmetov, Talant;Montes, Ruben;Sun, Jianan;Chen, Si-Han;Tang, Zhiye;Chang, Chia-en A.
了解配体结合动力学和热力学，包括研究自由，瞬态和最终的复杂构象，是重要的基础研究和应用化学和生物医学系统。除了实验确定的结构外，检查重要但短暂的配体-蛋白质结合构象也提供了对药物功效和选择性的更准确估计。此外，获得配体结合/解结合过程中的自由能景观的全貌是理解结合机制的关键。在这里，我们提出了一个结合动力学工具包（BKiT），其中包括几个实用程序来分析轨迹和计算自由能和动力学曲线。BKiT使用主成分空间来生成近似的非结合或构象转变坐标，用于准确描述和轻松可视化分子运动。我们实现了一种新的分区方法来分配索引沿着可以用作里程碑或微观状态的近似坐标。该程序可以生成输入文件来运行许多短的经典分子动力学模拟，并使用里程碑理论来构建自由能分布和估计结合停留时间。我们首先验证了该方法与主客体系统，阿司匹林从β-环糊精解结合，然后将该协议应用于吡唑化合物和细胞周期蛋白依赖性激酶8和细胞周期蛋白C复合物，一个激酶系统的药理学兴趣。总的来说，我们的方法取得了很好的协议与发表的结果，并建议配体设计策略。计算的解结合自由能景观也提供了一个更完整的图片配体-受体结合障碍和稳定的局部最小值加深我们对分子识别的理解。BKiT易于使用，并具有可扩展的功能，可用于将来扩展后分析和计算的实用程序。
Understanding ligand binding kinetics and thermodynamics, which involves investigating the free, transient and final complex conformations, is important in fundamental studies and applications for chemical and biomedical systems. Examining the important but transient ligand–protein-bound conformations, in addition to experimentally determined structures, also provides a more accurate estimation for drug efficacy and selectivity. Moreover, obtaining the entire picture of the free energy landscape during ligand binding/unbinding processes is critical in understanding binding mechanisms. Here, we present a Binding Kinetics Toolkit (BKiT) that includes several utilities to analyze trajectories and compute a free energy and kinetics profile. BKiT uses principal component space to generate approximated unbinding or conformational transition coordinates for accurately describing and easily visualizing the molecular motions. We implemented a new partitioning approach to assign indexes along the approximated coordinates that can be used as milestones or microstates. The program can generate input files to run many short classical molecular dynamics simulations and uses milestoning theory to construct the free energy profile and estimate binding residence time. We first validated the method with a host–guest system, aspirin unbinding from -cyclodextrin, and then applied the protocol to pyrazolourea compounds and cyclin-dependent kinase 8 and cyclin C complexes, a kinase system of pharmacological interest. Overall, our approaches yielded good agreement with published results and suggest ligand design strategies. The computed unbinding free energy landscape also provides a more complete picture of ligand–receptor binding barriers and stable local minima for deepening our understanding of molecular recognition. BKiT is easy to use and has extensible features for future expansion of utilities for post-analysis and calculations.
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DOI：
10.1002/wcms.1306
发表时间：
2017-07-01
影响因子：
11.4
作者：
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影响因子：
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影响因子：
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DOI：
10.1073/pnas.1301814110
发表时间：
2013-03-12
影响因子：
11.1
作者：
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通讯作者：
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