Hummer G, García A E, Garde S
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA.
Proteins. 2001 Jan 1;42(1):77-84.
We study the reversible folding/unfolding of short Ala and Gly-based peptides by molecular dynamics simulations of all-atom models in explicit water solvent. A kinetic analysis shows that the formation of a first alpha-helical turn occurs within 0.1-1 ns, in agreement with the analyses of laser temperature jump experiments. The unfolding times exhibit Arrhenius temperature dependence. For a rapidly nucleating all-Ala peptide, the helix nucleation time depends only weakly on temperature. For a peptide with enthalpically competing turn-like structures, helix nucleation exhibits an Arrhenius temperature dependence, corresponding to the unfolding of enthalpic traps in the coil ensemble. An analysis of structures in a "transition-state ensemble" shows that helix-to-coil transitions occur predominantly through breaking of hydrogen bonds at the helix ends, particularly at the C-terminus. The temperature dependence of the transition-state ensemble and the corresponding folding/unfolding pathways illustrate that folding mechanisms can change with temperature, possibly complicating the interpretation of high-temperature unfolding simulations. The timescale of helix formation is an essential factor in molecular models of protein folding. The rapid helix nucleation observed here suggests that transient helices form early in the folding event.
我们通过在明确的水溶剂中对全原子模型进行分子动力学模拟，研究了基于短丙氨酸（Ala）和甘氨酸（Gly）的肽的可逆折叠/去折叠过程。动力学分析表明，第一个α-螺旋转角的形成发生在0.1 - 1纳秒内，这与激光温度跳跃实验的分析结果一致。去折叠时间呈现出阿仑尼乌斯温度依赖性。对于一个快速成核的全丙氨酸肽，螺旋成核时间仅微弱地依赖于温度。对于一个具有焓竞争的类似转角结构的肽，螺旋成核呈现出阿仑尼乌斯温度依赖性，这对应于卷曲构象集合中焓阱的去折叠。对“过渡态集合”中的结构分析表明，螺旋到卷曲的转变主要通过螺旋末端特别是C末端的氢键断裂来发生。过渡态集合的温度依赖性以及相应的折叠/去折叠途径表明，折叠机制可能随温度变化，这可能会使高温去折叠模拟的解释变得复杂。螺旋形成的时间尺度是蛋白质折叠分子模型中的一个重要因素。这里观察到的快速螺旋成核表明，瞬态螺旋在折叠事件的早期形成。
