FIRST-PRINCIPLES CALCULATION OF THE FOLDING FREE-ENERGY OF A 3-HELIX BUNDLE PROTEIN
FIRST-PRINCIPLES CALCULATION OF THE FOLDING FREE-ENERGY OF A 3-HELIX BUNDLE PROTEIN
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DOI：
10.1126/science.7618103
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发表时间：
1995-07-21
期刊：
影响因子：
56.9
通讯作者：
BROOKS, CL
中科院分区：
文献类型：
--
作者：
BOCZKO, EM;BROOKS, CL
用分子动力学模拟、聚类分析和加权直方图技术研究了一个三螺旋束蛋白的折叠和去折叠过程。折叠-展开过程通过"折叠漏斗"发生，其中构象状态的均匀和广泛分布在天然流形之外。这种分布在过渡区附近变窄，并在原生流形内变得紧凑。折叠的关键热力学步骤包括围绕氨基末端螺旋-转角-螺旋基序的初始相互作用，螺旋I和II之间的相互作用，以及最后螺旋III对接到螺旋I-II亚结构域上。在计算的自由能表面的亚稳最小值观察到约1.5倍的原生体积。折叠-展开热力学主要受蛋白质-溶剂能量和总熵的相反影响，前者有利于展开，后者有利于通过疏水效应折叠。
The folding and unfolding of a three-helix bundle protein were explored with molecular-dynamics simulations, cluster analysis, and weighted-histogram techniques. The folding-unfolding process occurs by means of a ''folding funnel,'' in which a uniform and broad distribution of conformational states is accessible outside of the native manifold. This distribution narrows near a transition region and becomes compact within the native manifold. Key thermodynamic steps in folding include initial interactions around the amino-terminal helix-turn-helix motif, interactions between helices I and II, and, finally, the docking of helix III onto the helix I-II subdomain. A metastable minimum in the calculated free-energy surface is observed at approximately 1.5 times the native volume. Folding-unfolding thermodynamics are dominated by the opposing influences of protein-solvent energy, which favors unfolding, and the overall entropy, which favors folding by means of the hydrophobic effect.