KINETICS OF PROTEIN-FOLDING - A LATTICE MODEL STUDY OF THE REQUIREMENTS FOR FOLDING TO THE NATIVE-STATE
KINETICS OF PROTEIN-FOLDING - A LATTICE MODEL STUDY OF THE REQUIREMENTS FOR FOLDING TO THE NATIVE-STATE
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DOI：
10.1006/jmbi.1994.1110
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发表时间：
1994-02-04
影响因子：
5.6
通讯作者：
KARPLUS, M
中科院分区：
文献类型：
--
作者：
SALI, A;SHAKHNOVICH, E;KARPLUS, M
蛋白质的三维晶格模型被用来研究其折叠到天然状态所需的属性。多肽链表示为27珠杂聚物，其最低能量（天然）状态可以通过穷举所有完全紧凑的构象来确定。总共产生了260个具有随机相互作用的序列，并进行蒙特卡罗模拟，以确定哪些链在短时间内找到基态;即哪些序列克服了被称为莱文塔尔悖论的折叠问题。折叠和非折叠序列的比较用于识别快速折叠到全局能量最小所需的特征。它表明，成功的折叠不需要某些属性，以前已经提出的折叠所必需的，这些包括大量的shortvers-long-range接触在天然状态，高含量的二级结构在天然状态，天然接触地图和相互作用参数之间的强相关性，以及存在大量的低能量状态与近天然构象。相反，折叠序列和非折叠序列之间的本质区别是能谱的性质。在本模型中，序列快速折叠的充分必要条件是自然状态是明显的能量最小值。因此，折叠序列的天然状态的热力学稳定性对温度具有S形依赖性。这允许这样的序列满足折叠的热力学和动力学要求;即，在足够高的温度下，天然状态在热力学上占主导地位，以使折叠在动力学上成为可能。讨论了本结果对真实的蛋白质的适用性。
A three-dimensional lattice model of a protein is used to investigate the properties required for its folding to the native state. The polypeptide chain is represented as a 27 bead heteropolymer whose lowest energy (native) state can be determined by an exhaustive enumeration of all fully compact conformations. A total of 260 sequences with random interactions are generated and subjected to Monte Carlo simulations to determine which chains find the ground state in a short time; i.e. which sequences overcome the folding problem referred to as the Levinthal paradox. Comparison of the folding and non-folding sequences is used to identify the features that are required for fast folding to the global energy minimum. It is shown that successful folding doesnotrequire certain attributes that have been previously proposed as necessary for folding; these include a high number of shortversuslong-range contacts in the native state, a high content of the secondary structure in the native state, a strong correlation between the native contact map and the interaction parameters, and the existence of a high number of low energy states with near-native conformation. Instead, the essential difference between the folding and the non-folding sequences is the nature of the energy spectrum. The necessary and sufficient condition for a sequence to fold rapidly in the present model is that the native state is a pronounced energy minimum. As a consequence, the thermodynamic stability of the native state of a folding sequence has a sigmoidal dependence on temperature. This permits such a sequence to satisfy both the thermodynamic and the kinetic requirements for folding; i.e. the native state predominates thermodynamically at temperatures that are high enough for folding to be kinetically possible. The applicability of the present results to real proteins is discussed.