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在分子动力学模拟和实验中观察完整的压力跳跃蛋白重新折叠

Yanxin Liu¹, Maxim B Prigozhin, Klaus Schulten

¹Department of Physics, Beckman Institute, §Department of Chemistry, and ‡Center for Biophysics and Computational Biology, University of Illinois , Urbana, Illinois 61801, United States.

Journal of the American Chemical Society

|January 21, 2014

概括

在压力跳跃 (P-jump) 后蛋白质重新折叠是使用分子动力学 (MD) 模拟的. 一个 λ-抑制器突变体在 ~ 19 微秒内重新折叠,支持对蛋白质折叠动态的实验发现.

科学领域:

生物物理学的生物物理.
计算生物学计算生物学
蛋白质动力学蛋白质动力学

背景情况:

密度是分子动力学 (MD) 模拟中的可调节参数,使得压力跳跃 (P-jump) 诱导的蛋白质重新折叠成为MD的潜在基准.
虽然压力变质对二次结构的影响小于温度变质,但在快速P跳后重新折叠的动力学并不总是更快.
之前对λ-抑制器的实验显示了<3μs的爆发阶段和~1.5ms的缓慢阶段,后者归因于阻碍重新折叠的非本地螺旋结构.

研究的目的:

通过明确的溶剂分子动力学 (MD) 来研究 λ-抑制器突变的重新折叠路径和动力学.
为了确定MD模拟是否可以重现P跳诱导重新折叠所观察到的实验时间尺度.
阐明重新折叠过程背后的分子机制,特别是中间结构的作用.

主要方法:

执行一个单一的,明确的溶剂分子动力学 (MD) 模拟 λ-抑制器突变.
分析了大约19微秒的形状采样,以确定蛋白质重新折叠的途径.
在重新折叠的最后阶段,描述结构重排,包括螺旋和循环动力学.

主要成果:

一个 λ-抑制器突变物成功地在大约19微秒的单个MD轨迹内重新折叠.
生产性重新折叠到原始状态不是单一的事件,而是作为一系列螺旋和循环重排在约0.9微秒的时间内.
模拟结果与从近下坡折叠实验和在其他蛋白质中观察到的过渡状态过渡时间中推断出的分子时间尺度一致.

结论:

MD模拟可以在微秒时间尺度上捕捉蛋白质的重新折叠动态,支持P-jump诱导的重新折叠的实验观测.
观察到的重新折叠途径表明,P跳跃实验中的爆发阶段可以导致本地蛋白质的形成.
这项研究验证了MD模拟的使用,以了解蛋白质折叠机制和过渡状态.

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