Yunrui Qiu, Rafal P Wiewiora, Jesus A Izaguirre, Huafeng Xu, Woody Sherman, Weiping Tang, Xuhui Huang
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A significant challenge in PROTAC design is the screening of the linkers to induce favorable non-native PPIs between POI and E3 ligase. Here, we present a physics-based computational protocol to predict noncanonical and metastable PPI interfaces between an E3 ligase and a given POI, aiding in the design of linkers to stabilize the ternary complex and enhance degradation. Specifically, we build the non-Markovian dynamic model using the Integrative Generalized Master equation (IGME) method from ∼1.5 ms all-atom molecular dynamics simulations of linker-less encounter complex, to systematically explore the inherent PPIs between the oncogene homologue protein and the von Hippel-Lindau E3 ligase. Our protocol revealed six metastable states each containing a different PPI interface. We selected three of these metastable states containing promising PPIs for linker design. Our selection criterion included thermodynamic and kinetic stabilities of PPIs and the accessibility between the solvent-exposed sites on the warheads and E3 ligand. One selected PPIs closely matches a recent cocrystal PPI interface structure induced by an experimentally designed PROTAC with potent degradation efficacy. 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引用次数: 0
摘要
靶向蛋白质降解(TPD)正在成为一种治疗癌症和其他疾病的有前途的方法,越来越多的项目在人体临床试验中证明了它的疗效。蛋白水解靶向嵌合体(PROTACs)是TPD的一种显著方法,它通过E3连接酶诱导泛素化,然后进行蛋白酶体降解,从而选择性地降解感兴趣的蛋白质(POI)。PROTACs 采用弹头-连接体-配体结构,使 POI(与弹头结合)和 E3 连接酶(与配体结合)接近。由此在 POI 和 E3 连接酶之间形成的非原生蛋白-蛋白相互作用 (PPI) 导致形成稳定的三元复合物,增强了 TPD 的合作性。PROTAC 设计中的一个重大挑战是筛选连接体,以诱导 POI 和 E3 连接酶之间形成有利的非原生 PPI。在这里,我们提出了一种基于物理学的计算方案,用于预测 E3 连接酶与给定 POI 之间的非规范和可陨落 PPI 接口,从而帮助设计连接体,以稳定三元复合物并促进降解。具体来说,我们利用整合广义主方程(IGME)方法,从∼1.5毫秒的无连接体相遇复合物全原子分子动力学模拟中建立了非马尔可夫动态模型,系统地探索了癌基因同源蛋白与冯-希佩尔-林道E3连接酶之间固有的PPI。我们的方案揭示了六种陨变状态,每种状态都包含一个不同的 PPI 接口。我们选择了其中三个含有有希望的 PPI 的可变状态进行连接体设计。我们的选择标准包括 PPI 的热力学和动力学稳定性,以及弹头和 E3 配体上溶剂暴露位点之间的可达性。所选的一种 PPI 与最近由实验设计的 PROTAC 诱导的共晶体 PPI 接口结构非常吻合,具有很强的降解功效。我们预计,我们的方案在预测可陨落的 POI-配体界面方面具有巨大的广泛应用潜力,可以帮助合理设计 PROTAC。
Targeted protein degradation (TPD) is emerging as a promising therapeutic approach for cancer and other diseases, with an increasing number of programs demonstrating its efficacy in human clinical trials. One notable method for TPD is Proteolysis Targeting Chimeras (PROTACs) that selectively degrade a protein of interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize a warhead-linker-ligand architecture to bring the POI (bound to the warhead) and the E3 ligase (bound to the ligand) into proximity. The resulting non-native protein-protein interactions (PPIs) formed between the POI and E3 ligase lead to the formation of a stable ternary complex, enhancing cooperativity for TPD. A significant challenge in PROTAC design is the screening of the linkers to induce favorable non-native PPIs between POI and E3 ligase. Here, we present a physics-based computational protocol to predict noncanonical and metastable PPI interfaces between an E3 ligase and a given POI, aiding in the design of linkers to stabilize the ternary complex and enhance degradation. Specifically, we build the non-Markovian dynamic model using the Integrative Generalized Master equation (IGME) method from ∼1.5 ms all-atom molecular dynamics simulations of linker-less encounter complex, to systematically explore the inherent PPIs between the oncogene homologue protein and the von Hippel-Lindau E3 ligase. Our protocol revealed six metastable states each containing a different PPI interface. We selected three of these metastable states containing promising PPIs for linker design. Our selection criterion included thermodynamic and kinetic stabilities of PPIs and the accessibility between the solvent-exposed sites on the warheads and E3 ligand. One selected PPIs closely matches a recent cocrystal PPI interface structure induced by an experimentally designed PROTAC with potent degradation efficacy. We anticipate that our protocol has significant potential for widespread application in predicting metastable POI-ligase interfaces that can enable rational design of PROTACs.