Application of per-Residue Energy Decomposition to Design Peptide Inhibitors of PSD95 GK Domain.
Application of per-Residue Energy Decomposition to Design Peptide Inhibitors of PSD95 GK Domain.
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DOI：
10.3389/fmolb.2022.848353
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
作者：
突触后密度蛋白95（PSD 95）和突触相关蛋白90/突触后密度蛋白95相关蛋白（SAPAP）之间的特异性相互作用对兴奋性突触发育和可塑性至关重要。设计靶向PSD 95鸟苷酸激酶（GK）结构域的抑制剂是研究PSD 95 GK功能及其相关精神疾病病因学的一种有前途的操作工具。本文通过分子动力学模拟，设计了具有更高亲和力的PSD 95 GK/SAPAP新肽抑制剂。首先，通过分子动力学模拟研究了PSD 95 GK与磷酸化和非磷酸化多肽的相互作用。除了由磷酸丝氨酸（p-Ser）或相应的拟磷酸残基Asp/Glu介导的氢键相互作用外，来自其他氨基酸的疏水相互作用也有助于PSD 95 GK/SAPAP相互作用。作为一种具有中等结合亲和力和相对较低分子量的非磷酸化合成肽，选择QSF抑制肽进行进一步修饰。根据PSD 95 GK/QSF复合物的单残基能量分解结果，设计了10个增强结合作用的多肽，特别是增强疏水作用。最终合成了结合能较低的前五个肽。使用荧光偏振（FP）测定法测定合成肽的结合亲和力。如预期的，所有肽具有比QSF肽更高的结合亲和力（Ki = 5.64 ± 0.51 μM）。其中，F10 W的抑制活性最强（Ki = 0.75 ± 0.25 μM），表明增强疏水相互作用是设计靶向PSD 95 GK的新型抑制肽的重要策略。
Specific interaction between the postsynaptic density protein 95 (PSD95) and synapse-associated protein 90/postsynaptic density 95–associated protein (SAPAP) is crucial for excitatory synaptic development and plasticity. Designing inhibitors that target the guanylate kinase (GK) domain of PSD95, which is responsible for the interaction, is a promising manipulation tool for the investigation of the function of PSD95 GK and the etiology of its related psychiatric disorders. Herein, we designed new peptide inhibitors of PSD95 GK/SAPAP with higher binding affinity by using molecular dynamics simulations. First, the interactions between PSD95 GK and their reported phosphorylated and unphosphorylated peptides were explored by molecular dynamics simulations. Besides the hydrogen bonding interactions mediated by the phospho-serine (p-Ser) or corresponding phosphomimic residue Asp/Glu, the hydrophobic interactions from the other amino acids also contribute to the PSD95 GK/SAPAP interaction. As an unphosphorylated synthetic peptide with moderate binding affinity and relatively lower molecular weight, the QSF inhibitory peptide was selected for further modification. Based on per-residue energy decomposition results of the PSD95 GK/QSF complex, ten peptides were designed to enhance the binding interactions, especially the hydrophobic interactions. The top-ranked five peptides with lower binding energy were eventually synthesized. The binding affinities of the synthesized peptides were determined using fluorescence polarization (FP) assay. As expected, all peptides have higher binding affinity than the QSF peptide (K i = 5.64 ± 0.51 μM). Among them, F10W was the most potent inhibitor (K i = 0.75 ± 0.25 μM), suggesting that enhancement of the hydrophobic interactions is an important strategy for the design of new inhibitory peptides targeting PSD95 GK.
影响因子：
3.7
作者：
Balan S;Yamada K;Hattori E;Iwayama Y;Toyota T;Ohnishi T;Maekawa M;Toyoshima M;Iwata Y;Suzuki K;Kikuchi M;Yoshikawa T
通讯作者：
Yoshikawa T