Core Binding Site of a Thioflavin-T-Derived Imaging Probe on Amyloid β Fibrils Predicted by Computational Methods,ACS Chemical Neuroscience

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Core Binding Site of a Thioflavin-T-Derived Imaging Probe on Amyloid β Fibrils Predicted by Computational Methods
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-01-30 00:00:00 , DOI: 10.1021/acschemneuro.7b00389
Ryoko Kawai ₁ , Mitsugu Araki _{2,

3} , Masashi Yoshimura ₁ , Narutoshi Kamiya ₄ , Masahiro Ono ₁ , Hideo Saji ₁ , Yasushi Okuno _{2,

3}

Affiliation

Development of new diagnostic imaging probes for Alzheimer’s disease, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) probes, has been strongly desired. In this study, we investigated the most accessible amyloid β (Aβ) binding site of [¹²³I]IMPY, a Thioflavin-T-derived SPECT probe, using experimental and computational methods. First, we performed a competitive inhibition assay with Orange-G, which recognizes the KLVFFA region in Aβ fibrils, suggesting that IMPY and Orange-G bind to different sites in Aβ fibrils. Next, we precisely predicted the IMPY binding site on a multiple-protofilament Aβ fibril model using computational approaches, consisting of molecular dynamics and docking simulations. We generated possible IMPY-binding structures using docking simulations to identify candidates for probe-binding sites. The binding free energy of IMPY with the Aβ fibril was calculated by a free energy simulation method, MP-CAFEE. These computational results suggest that IMPY preferentially binds to an interfacial pocket located between two protofilaments and is stabilized mainly through hydrophobic interactions. Finally, our computational approach was validated by comparing it with the experimental results. The present study demonstrates the possibility of computational approaches to screen new PET/SPECT probes for Aβ imaging.

中文翻译：

硫黄素-T衍生的成像探针在淀粉样β原纤维上的核心结合位点的计算方法预测。

迫切需要开发用于阿尔茨海默氏病的新型诊断成像探针，例如正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）探针。在这项研究中，我们研究了[ ¹²³I] IMPY，硫黄素T衍生的SPECT探针，使用实验和计算方法。首先，我们用Orange-G进行了竞争性抑制试验，该试验可识别Aβ原纤维中的KLVFFA区域，表明IMPY和Orange-G结合于Aβ原纤维中的不同位点。接下来，我们使用包括分子动力学和对接模拟在内的计算方法，精确地预测了多原丝Aβ原纤维模型上的IMPY结合位点。我们使用对接模拟生成了可能的IMPY结合结构，以识别探针结合位点的候选物。通过自由能模拟方法MP-CAFEE计算IMPY与Aβ原纤维的结合自由能。这些计算结果表明，IMPY优先结合到位于两个原丝之间的界面袋，并且主要通过疏水相互作用来稳定。最后，通过将其与实验结果进行比较来验证我们的计算方法。本研究证明了计算方法筛选用于Aβ成像的新型PET / SPECT探针的可能性。

更新日期：2018-01-30

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