Flexible Fitting of Biomolecular Structures to Atomic Force Microscopy Images via Biased Molecular Simulations
Flexible Fitting of Biomolecular Structures to Atomic Force Microscopy Images via Biased Molecular Simulations
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DOI：
10.1021/acs.jctc.9b00991
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发表时间：
2020-02-01
影响因子：
5.5
通讯作者：
Takada, Shoji
中科院分区：
文献类型：
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作者：
Niina, Toni;Fuchigami, Sotaro;Takada, Shoji
高速原子力显微镜（High-speed atomic force microscopy，简称HS）是一种能够在接近生理状态下观察生物分子大尺度结构动力学的重要成像技术，但其数据仅限于样品的表面形状。刚体拟合方法被开发以获得适合AFM图像的分子结构，而不考虑构象变化。在这里，我们开发了一种方法，以适应灵活的三维（3D）生物分子结构到AFM图像。首先，我们描述了一种方法来产生一个伪AFM图像从一个给定的三维结构中的一个可微的形式。然后，使用实验AFM图像和计算伪AFM图像之间的相关函数，我们开发了一种灵活的拟合分子动力学（MD）模拟方法，通过该方法，我们得到的蛋白质结构，以及适合给定的AFM图像。我们首先测试它与一个双胞胎实验;使用AFM图像产生的蛋白质结构不同于其天然构象作为参考，我们进行了灵活的拟合MD模拟样品的构象，以及适合的参考AFM图像，该方法被证实工作良好。讨论了协议中的参数依赖性。最后，我们将该方法应用到一个真实的实验HS-AFM图像的鞭毛蛋白FlhA，证明其适用性。我们还测试了原子力显微镜图像的分子结构的刚体拟合。我们的方法将是一个通用的工具，动态结构建模的基础上HS-AFM图像，并公开通过CafeMol软件。
High-speed (HS) atomic force microscopy (AFM) is a prominent imaging technology that observes large-scale structural dynamics of biomolecules near the physiological condition, but the AFM data are limited to the surface shape of specimens. Rigid-body fitting methods were developed to obtain molecular structures that fit to an AFM image, without accounting for conformational changes. Here, we developed a method to fit flexibly a three-dimensional (3D) biomolecular structure into an AFM image. First, we describe a method to produce a pseudo-AFM image from a given 3D structure in a differentiable form. Then, using a correlation function between the experimental AFM image and the computational pseudo-AFM image, we developed a flexible fitting molecular dynamics (MD) simulation method by which we obtain protein structures that well fit to the given AFM image. We first test it with a twin experiment; using an AFM image produced from a protein structure different from its native conformation as a reference, we performed the flexible fitting MD simulations to sample conformations that fit well the reference AFM image, and the method was confirmed to work well. Then, parameter dependence in the protocol was discussed. Finally, we applied the method to a real experimental HS-AFM image for a flagellar protein FlhA, demonstrating its applicability. We also test the rigid-body fitting of a molecular structure to an AFM image. Our method will be a general tool for dynamic structure modeling based on HS-AFM images and is publicly available through the CafeMol software.