Structure-based conformational preferences of amino acids
Structure-based conformational preferences of amino acids
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DOI：
10.1073/pnas.96.22.12524
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Levitt, M
中科院分区：
文献类型：
--
作者：
Koehl, P;Levitt, M
蛋白质对氨基酸取代的耐受性很强，即使是在它们的核心。了解导致这种行为的因素对蛋白质工程和设计至关重要。蛋白质的突变已经根据它们所引起的稳定性变化进行了量化。例如，特定二级结构中的客体残基已被用作氨基酸构象偏好的探针，从而产生倾向尺度。预测这些氨基酸的倾向将是对任何用于模拟蛋白质稳定性的新势能函数的一个很好的测试。我们最近开发了一种蛋白质设计程序，该程序基于模板主链和半经验势能函数的知识，为给定的目标构象优化鲸鱼序列。这个能量函数是纯物理的，包括基于伦纳德-琼斯势的立体相互作用，基于库仑势的静电，以及基于可达表面积和原子间接触面积的环境自由能形式的疏水性。利用该程序设计的序列对10种不同的蛋白质进行了分析，以提取氨基酸的构象偏好。所得的基于结构的倾向量表与实验倾向量表值有显著的一致性，无论是对于螺旋还是p -sheet。这些结果表明，氨基酸的构象偏好是我们使用势能的自然结果。这证实了我们潜力的准确性，并表明这种偏好不应该被添加为设计标准。
Proteins can he very tolerant to amino acid substitution, even within their core. Understanding the factors responsible for this behavior is of critical importance for protein engineering and design. Mutations in proteins have been quantified in terms of the changes in stability they induce. For example, guest residues in specific secondary structures have been used as probes of conformational preferences of amino acids, yielding propensity scales. Predicting these amino acid propensities would be a good test of any new potential energy functions used to mimic protein stability. We have recently developed a protein design procedure that optimizes whale sequences for a given target conformation based on the knowledge of the template backbone and on a semiempirical potential energy function. This energy function is purely physical, including steric interactions based on a Lennard-Jones potential, electrostatics based on a Coulomb potential, and hydrophobicity in the form of an environment free energy based on accessible surface area and interatomic: contact areas. Sequences designed by this procedure for 10 different proteins were analyzed to extract conformational preferences for amino acids. The resulting structure-based propensity scales show significant agreements with experimental propensity scale values, both for cr-helices and P-sheets. These results indicate that amino acid conformational preferences are a natural consequence of the potential energy we use. This confirms the accuracy of our potential and indicates that such preferences should not be added as a design criterion.