Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131, USA.
Albuquerque Academy, Albuquerque, NM 87131, USA.
Cells. 2022 Aug 7;11(15):2451. doi: 10.3390/cells11152451.
The PDZ family has drawn attention as possible drug targets because of the domains' wide ranges of function and highly conserved binding pockets. The PICK1 PDZ domain has been proposed as a possible drug target because the interactions between the PICK1 PDZ domain and the GluA2 subunit of the AMPA receptor have been shown to progress neurodegenerative diseases. BIO124 has been identified as a sub µM inhibitor of the PICK1-GluA2 interaction. Here, we use all-atom molecular dynamics simulations to reveal the atomic-level interaction pattern between the PICK1 PDZ domain and BIO124. Our simulations reveal three unique binding conformations of BIO124 in the PICK1 PDZ binding pocket, referred to here as state 0, state 1, and state 2. Each conformation is defined by a unique hydrogen bonding network and a unique pattern of hydrophobic interactions between BIO124 and the PICK1 PDZ domain. Interestingly, each conformation of BIO124 results in different dynamic changes to the PICK1 PDZ domain. Unlike states 1 and 2, state 0 induces dynamic coupling between BIO124 and the αA helix. Notably, this dynamic coupling with the αA helix is similar to what has been observed in other PDZ-ligand complexes. Our analysis indicates that the interactions formed between BIO124 and I35 may be the key to inducing dynamic coupling with the αA helix. Lastly, we suspect that the conformational shifts observed in our simulations may affect the stability and thus the overall effectiveness of BIO124. We propose that a physically larger inhibitor may be necessary to ensure sufficient interactions that permit stable binding between a drug and the PICK1 PDZ domain.
PDZ 家族因其结构域广泛的功能和高度保守的结合口袋而引起了人们的关注，被认为是可能的药物靶点。PICK1 PDZ 结构域被认为是一个可能的药物靶点，因为已经证明 PICK1 PDZ 结构域与 AMPA 受体的 GluA2 亚基之间的相互作用会导致神经退行性疾病的进展。BIO124 已被确定为 PICK1-GluA2 相互作用的亚微摩尔抑制剂。在这里，我们使用全原子分子动力学模拟来揭示 PICK1 PDZ 结构域与 BIO124 之间的原子级相互作用模式。我们的模拟揭示了 BIO124 在 PICK1 PDZ 结合口袋中的三种独特结合构象，这里分别称为状态 0、状态 1 和状态 2。每种构象都由独特的氢键网络和 BIO124 与 PICK1 PDZ 结构域之间独特的疏水性相互作用模式定义。有趣的是，BIO124 的每种构象都会导致 PICK1 PDZ 结构域的不同动态变化。与状态 1 和状态 2 不同，状态 0 会导致 BIO124 与αA 螺旋之间产生动态耦合。值得注意的是，这种与αA 螺旋的动态耦合与在其他 PDZ-配体复合物中观察到的类似。我们的分析表明，BIO124 与 I35 之间形成的相互作用可能是与αA 螺旋产生动态耦合的关键。最后，我们怀疑模拟中观察到的构象变化可能会影响 BIO124 的稳定性，从而影响其整体效果。我们提出，更大的结构更合理的抑制剂可能是确保药物与 PICK1 PDZ 结构域之间稳定结合所必需的。
