Breaking non-native hydrophobic clusters is the rate-limiting step in the folding of an alanine-based peptide
Breaking non-native hydrophobic clusters is the rate-limiting step in the folding of an alanine-based peptide
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DOI：
10.1002/bip.10216
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发表时间：
2003-01-01
期刊：
影响因子：
2.9
通讯作者：
Duan, Y
中科院分区：
文献类型：
--
作者：
Chowdhury, S;Zhang, W;Duan, Y
利用最近开发的全原子点电荷力场和有效盐浓度为 0.2M 的广义玻恩连续溶剂模型，通过全原子分子动力学模拟研究了基于丙氨酸的肽的形成机制。进行了 32 次模拟，每次模拟持续 100 ns。观察到了令人惊讶的复杂折叠过程。螺旋内容物的发展可分为三个阶段，时间常数分别为0.06-0.08、1.4-2.3和12-13 ns。螺旋在第一阶段中启动得非常快，类似于从显式溶剂模拟中估计的结果。疏水塌陷也发生在这个阶段。折叠中间状态在第二阶段形成，并在第三阶段展开以使肽达到过渡状态。折叠中间态的特征是双匝短螺旋，过渡态是螺旋-转角-螺旋基序——两者都由疏水簇稳定。通过主链Phi-Psi扭转角和主链氢键计算得出的平衡螺旋含量为64-66%，与实验结果非常吻合。校正溶剂粘度影响后，获得 16-20 ns 的外推折叠时间，这与实验定性一致。与普遍观点相反，螺旋的起始和增长都不是限速步骤。相反，该肽的限速步骤是破坏非天然疏水簇以达到过渡状态。还讨论了对蛋白质折叠机制的影响。 (C) 2002 年 Wiley 期刊公司
The formation mechanism of an alanine-based peptide has been studied by all-atom molecular dynamics simulations with a recently developed all-atom point-charge force field and the Generalize Born continuum solvent model at an effective salt concentration of 0.2M. Thirty-two simulations were conducted Each simulation was performed for 100 ns. A surprisingly complex folding process was observed. The development of the helical content can be divided into three phases with time constants of 0.06-0.08, 1.4-2.3, and 12-13 ns, respectively. Helices initiate extreme rapidly in the first phase similar to that estimated from explicit solvent simulations. Hydrophobic collapse also takes place in this phase. A folding intermediate state develops in the second phase and is unfolded to allow the peptide to reach the transition state in the third phase. The folding intermediate states are characterized by the two-turn short helices and the transition states are helix-turn-helix motifs-both of which are stabilized by hydrophobic clusters. The equilibrium helical content, calculated by both the main-chain Phi-Psi torsion angles and the main-chain hydrogen bonds, is 64-66%, which is in remarkable agreement with experiments. After corrected for the solvent viscosity effect, an extrapolated folding time of 16-20 ns is obtained that is in qualitative agreement with experiments. Contrary to the prevailing opinion, neither initiation nor growth of the helix is the rate-limiting step. Instead, the rate-limiting step for this peptide is breaking the non-native hydrophobic clusters in order to reach the transition state. The implication to the folding mechanisms of proteins is also discussed. (C) 2002 Wiley Periodicals, Inc.