Biophysical and structural considerations for protein sequence evolution.
Biophysical and structural considerations for protein sequence evolution.
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DOI：
10.1186/1471-2148-11-361
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发表时间：
2011-12-16
影响因子：
3.4
通讯作者：
Liberles DA
中科院分区：
文献类型：
--
作者：
Grahnen JA;Nandakumar P;Kubelka J;Liberles DA
蛋白质序列进化受到折叠和功能的生物物理学限制，导致序列中相互作用位点之间存在相互依存关系。然而，当前位点独立的序列进化模型并未考虑到这一点。近期通过统计/信息方法将结构和生物物理学的影响整合到系统发育模型中的尝试，并未使模型性能得到预期的改善。这表明该领域的进展需要进一步创新。
在此，我们开发了一个基于粗粒度物理学的蛋白质折叠和结合功能模型，并将其与一个流行的信息模型进行比较。我们发现这两个模型都违背了天然序列接近热力学最优的假设，导致偏离天然状态的定向选择。抽样和模拟表明，基于物理学的模型对确定折叠的相互作用更具特异性，这些相互作用在残基类型之间变化较小。信息模型在序列空间中扩散得更远，障碍更少，并且往往对不变位点模型提供的支持较少，尽管氨基酸替换通常是保守的。这两种方法产生的序列都具有自然特征，如位点间的dN/dS < 1以及呈伽马分布的速率。
简单的蛋白质折叠粗粒度模型可以描述进化中蛋白质的一些自然特征，但目前不够准确，无法用于进化推断。这部分是由于疏水核心的不当堆积。我们就天然和非天然构象提出了在结构、折叠能和结合功能表示方面可能的改进，并描述了这种模型的大量可能应用。
Protein sequence evolution is constrained by the biophysics of folding and function, causing interdependence between interacting sites in the sequence. However, current site-independent models of sequence evolutions do not take this into account. Recent attempts to integrate the influence of structure and biophysics into phylogenetic models via statistical/informational approaches have not resulted in expected improvements in model performance. This suggests that further innovations are needed for progress in this field. Here we develop a coarse-grained physics-based model of protein folding and binding function, and compare it to a popular informational model. We find that both models violate the assumption of the native sequence being close to a thermodynamic optimum, causing directional selection away from the native state. Sampling and simulation show that the physics-based model is more specific for fold-defining interactions that vary less among residue type. The informational model diffuses further in sequence space with fewer barriers and tends to provide less support for an invariant sites model, although amino acid substitutions are generally conservative. Both approaches produce sequences with natural features like dN/dS < 1 and gamma-distributed rates across sites. Simple coarse-grained models of protein folding can describe some natural features of evolving proteins but are currently not accurate enough to use in evolutionary inference. This is partly due to improper packing of the hydrophobic core. We suggest possible improvements on the representation of structure, folding energy, and binding function, as regards both native and non-native conformations, and describe a large number of possible applications for such a model.
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影响因子：
2.2
作者：
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影响因子：
3.3
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影响因子：
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影响因子：
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作者：
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通讯作者：
Goldstein, Richard A.
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影响因子：
3
作者：
Feng Y;Kloczkowski A;Jernigan RL
通讯作者：
Jernigan RL