pH-Dependent Population Shift Regulates BACE1 Activity and Inhibition.
pH-Dependent Population Shift Regulates BACE1 Activity and Inhibition.
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DOI：
10.1021/jacs.5b05891
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发表时间：
2015-08-05
影响因子：
15
通讯作者：
Shen J
中科院分区：
文献类型：
--
作者：
Ellis CR;Shen J
BACE1是治疗阿尔茨海默病的主要治疗靶点，其作用范围很窄。尽管在BACE1抑制剂的开发方面做出了巨大的努力并取得了进展，但其潜在的pH依赖调节机制的细节仍不清楚。在这里，我们用连续恒定的pH分子动力学阐明了调节BACE1活性的依赖于pH的构象机制。模拟结果表明，BACE1主要占据三种构象状态，但其相对布居数随pH的变化而变化。在中等pH时，当催化二聚体是单质子化时，结合活性状态很高，而在低pH和高pH时，Tyr抑制状态占主导地位。此外，我们的数据提供了强有力的证据支持构象选择作为底物和多肽抑制物结合的主要机制。这些新的见解，虽然与实验一致，但极大地扩展了BACE1的知识，并对进一步优化抑制剂和了解靶向BACE1的潜在副作用具有意义。最后，这项工作强调了在分子动力学模拟中正确模拟质子化状态的重要性。
BACE1, a major therapeutic target for treatment of Alzheimer’s disease, functions within a narrow pH range. Despite tremendous effort and progress in the development of BACE1 inhibitors, details of the underlying pH-dependent regulatory mechanism remain unclear. Here we elucidate the pH-dependent conformational mechanism that regulates BACE1 activity using continuous constant pH molecular dynamics. The simulations reveal that BACE1 mainly occupies three conformational states, however, the relative population of the states shifts according to pH. At intermediate pH when the catalytic dyad is mono-protonated, a binding-competent state is highly populated, while at low and high pH a Tyr-inhibited state is dominant. Furthermore, our data provide strong evidence supporting conformational selection as a major mechanism for substrate and peptide-inhibitor binding. These new insights, while consistent with experiment, greatly extend the knowledge of BACE1 and have implications for further optimization of inhibitors and understanding potential side effects of targeting BACE1. Finally, the work highlights the importance of properly modeling protonation states in molecular dynamics simulations.