Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding
Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding
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DOI：
10.1063/5.0021399
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发表时间：
2020-10-21
影响因子：
4.4
通讯作者：
Miao, Yinglong
中科院分区：
文献类型：
--
作者：
Wang, Jinan;Miao, Yinglong
在高等真核生物中，多肽介导了高达40%的已知蛋白质-蛋白质相互作用，并在细胞信号转导中发挥着重要作用。然而，由于多肽具有较长的生物时间尺度和极高的柔韧性，通过传统的分子动力学模拟多肽的结合和解离以及计算多肽结合自由能是一项具有挑战性的工作。基于高斯加速分子动力学(GAMD)增强采样技术，我们发展了一种新的计算方法“PEP-GAMD”，它选择性地提高多肽的基本势能，以便有效地模拟其高灵活性。此外，在双Boost算法中，将另一个Boost势应用于整个系统的剩余势能。PEP-GAMD已经证实了三个模型多肽与SH3结构域的结合。独立的1亩S双Boost PEP-GAMD模拟捕捉到了重复的多肽解离和结合事件，这使得我们能够计算多肽结合的热力学和动力学。计算的结合自由能和动力学速率常数与已有的实验数据符合得很好。此外，全原子的PEP-GAMD模拟对多肽与蛋白质结合的机制提供了重要的见解，这些机制涉及远程静电相互作用和主要的构象选择。总而言之，PEP-GAMD提供了一种高效、易用的方法，用于不受约束的增强采样和多肽结合自由能和动力学的计算。
Peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play an important role in cellular signaling. However, it is challenging to simulate both binding and unbinding of peptides and calculate peptide binding free energies through conventional molecular dynamics, due to long biological timescales and extremely high flexibility of the peptides. Based on the Gaussian accelerated molecular dynamics (GaMD) enhanced sampling technique, we have developed a new computational method "Pep-GaMD," which selectively boosts essential potential energy of the peptide in order to effectively model its high flexibility. In addition, another boost potential is applied to the remaining potential energy of the entire system in a dual-boost algorithm. Pep-GaMD has been demonstrated on binding of three model peptides to the SH3 domains. Independent 1 mu s dual-boost Pep-GaMD simulations have captured repetitive peptide dissociation and binding events, which enable us to calculate peptide binding thermodynamics and kinetics. The calculated binding free energies and kinetic rate constants agreed very well with available experimental data. Furthermore, the all-atom Pep-GaMD simulations have provided important insights into the mechanism of peptide binding to proteins that involves long-range electrostatic interactions and mainly conformational selection. In summary, Pep-GaMD provides a highly efficient, easy-to-use approach for unconstrained enhanced sampling and calculations of peptide binding free energies and kinetics.