Positive and negative design in stability and thermal adaptation of natural proteins.
Positive and negative design in stability and thermal adaptation of natural proteins.
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天然蛋白质的稳定性和热适应性的正面设计。
DOI：
10.1371/journal.pcbi.0030052
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发表时间：
2007-03-23
影响因子：
4.3
通讯作者：
Shakhnovich, Eugene I.
中科院分区：
文献类型：
--
作者：
Berezovsky, Igor N.;Zeldovich, Konstantin B.;Shakhnovich, Eugene I.
这项工作的目的是阐明蛋白质设计的物理原理如何反映在响应环境热条件而进化的自然序列中。使用精确可解的晶格模型，我们设计具有选定热属性的序列。对设计的模型序列和天然蛋白质组的组成分析揭示了氨基酸组成的特定趋势，以响应升高的环境温度下的稳定性要求：疏水性和带电氨基酸残基的分数增加，而极性氨基酸残基的分数增加。我们表明，这种“从疏水性尺度的两端”的趋势是由于蛋白质设计的积极（稳定天然状态）和消极（破坏错误折叠状态）成分造成的。负设计强化了错误折叠结构中出现的特定排斥性非原生相互作用。在非天然构象中保留特定排斥相互作用的压力可能会导致在天然状态下相距很远但在错误折叠构象中可能接触的氨基酸之间发生相关突变。这种相关突变确实存在于 TIM 桶和其他蛋白质中。大自然在寻找嗜热蛋白质时使用了什么机制？众所周知，蛋白质的稳定性主要取决于天然状态和一组错误折叠（错误折叠）构象之间的能隙或能量差异。在这里，我们证明大自然通过扩大两端的间隙来制造嗜热蛋白质。通过在天然状态下接触的位置选择具有强烈吸引力的氨基酸来降低蛋白质天然状态的能量（正设计）。同时，通过选择远离天然结构的位置处的强排斥性氨基酸，错误折叠构象的能量增加；然而，这些氨基酸会在错误折叠构象（负设计）中相互排斥。蛋白质设计的这些基本原则体现在嗜热适应中观察到的“疏水性尺度的两端”趋势中，即嗜热蛋白质的蛋白质组富含极端氨基酸（疏水性和带电），但牺牲了极性氨基酸。疏水性氨基酸主要有助于正向设计，而在蛋白质的非天然构象中相互排斥的带电氨基酸则有助于负向设计。我们的结果为合理设计具有选定热特性的蛋白质提供了指导。
The aim of this work is to elucidate how physical principles of protein design are reflected in natural sequences that evolved in response to the thermal conditions of the environment. Using an exactly solvable lattice model, we design sequences with selected thermal properties. Compositional analysis of designed model sequences and natural proteomes reveals a specific trend in amino acid compositions in response to the requirement of stability at elevated environmental temperature: the increase of fractions of hydrophobic and charged amino acid residues at the expense of polar ones. We show that this “from both ends of the hydrophobicity scale” trend is due to positive (to stabilize the native state) and negative (to destabilize misfolded states) components of protein design. Negative design strengthens specific repulsive non-native interactions that appear in misfolded structures. A pressure to preserve specific repulsive interactions in non-native conformations may result in correlated mutations between amino acids that are far apart in the native state but may be in contact in misfolded conformations. Such correlated mutations are indeed found in TIM barrel and other proteins. What mechanisms does Nature use in her quest for thermophilic proteins? It is known that stability of a protein is mainly determined by the energy gap, or the difference in energy, between native state and a set of incorrectly folded (misfolded) conformations. Here we show that Nature makes thermophilic proteins by widening this gap from both ends. The energy of the native state of a protein is decreased by selecting strongly attractive amino acids at positions that are in contact in the native state (positive design). Simultaneously, energies of the misfolded conformations are increased by selection of strongly repulsive amino acids at positions that are distant in native structure; however, these amino acids will interact repulsively in the misfolded conformations (negative design). These fundamental principles of protein design are manifested in the “from both ends of the hydrophobicity scale” trend observed in thermophilic adaptation, whereby proteomes of thermophilic proteins are enriched in extreme amino acids—hydrophobic and charged—at the expense of polar ones. Hydrophobic amino acids contribute mostly to the positive design, while charged amino acids that repel each other in non-native conformations of proteins contribute to negative design. Our results provide guidance in rational design of proteins with selected thermal properties.
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影响因子：
56.9
作者：
Dahiyat, BI;Mayo, SL
通讯作者：
Mayo, SL
DOI：
10.1073/pnas.0506124102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Bolon, DN;Grant, RA;Sauer, RT
通讯作者：
Sauer, RT
DOI：
10.1073/pnas.89.11.4918
发表时间：
1992-06-01
影响因子：
11.1
作者：
GOLDSTEIN, RA;LUTHEYSCHULTEN, ZA;WOLYNES, PG
通讯作者：
WOLYNES, PG
影响因子：
8.6
作者：
Li, H;Tang, C;Wingreen, NS
通讯作者：
Wingreen, NS
影响因子：
3
作者：
Lassmann T;Sonnhammer EL
通讯作者：
Sonnhammer EL