准确预测药物耐药性对于内在无序的蛋白质区域
Audrius Kalpokas1, Mark Mackey2, Julien Michel1
1EaStCHEM School of Chemistry, The University of Edinburgh, Edinburgh EH9 3FJ, U.K.
Journal of chemical theory and computation
|December 5, 2025
概括
自由能量扰动 (FEP) 协议准确地预测了对内在无序区域 (IDRs) 的连接对象的突变效应. 平衡FEP方法对这些动态蛋白质区域显示出卓越的精度.
科学领域:
- 计算化学是一种计算化学.
- 结构生物学是结构生物学.
- 生物物理学的生物物理.
背景情况:
- 化学自由能量计算,如自由能量扰动 (FEP),对于预测氨基酸突变如何影响连接物结合亲缘关系非常有价值.
- 对于具有内在无序区域 (IDR) 的蛋白质,既定的FEP协议并不容易获得,这些区域对于各种生物过程至关重要.
- 众所周知,MDM2的N-终端内在无序区域 (IDR) 盖面经历了依赖联体的折叠,这使得它成为计算研究中具有挑战性的系统.
研究的目的:
- 开发和验证可靠的FEP协议,以准确预测MDM2突变体对AM-7209和Nutlin-3a联体的实验性结合亲缘关系.
- 评估平衡和不平衡化学FEP协议的性能,特别是对于涉及IDR自由度缓慢变化的突变.
- 研究蛋白质力场和水模型对灵活IDR区域模拟的影响.
主要方法:
- 使用相对化学结合的自由能量计算,特别是自由能量扰动 (FEP).
- 对一个MDM2突变组的平衡和不平衡化学FEP协议进行比较.
- 系统地评估了不同蛋白质力场和水模型对IDR的FEP计算的影响.
主要成果:
- 与非平衡协议相比,平衡FEP协议在自由能量估计中表现出更高的精度.
- 该研究确定了蛋白质力场和水模型选择对模拟灵活IDR的显著影响.
- 开发的FEP协议成功地复制了MDM2突变体的实验性结合亲和趋势.
结论:
- 开发了一个准确的FEP协议,适用于内在无序的蛋白质区域.
- 证明了平衡FEP的有效性,用于预测动态IDR中对联体结合亲和力的突变效应.
- 强调选择适当的力场和水模型来模拟灵活的IDR系统的重要性.
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