Probing designability via a generalized model of helical bundle geometry.
Probing designability via a generalized model of helical bundle geometry.
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DOI：
10.1016/j.jmb.2010.08.058
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发表时间：
2011-01-28
影响因子：
5.6
通讯作者：
Degrado WF
中科院分区：
文献类型：
--
作者：
Grigoryan G;Degrado WF
由于折叠蛋白质结构的空间高度简并，具有反复出现的二级和三级结构基序，用具有物理相关性的集合坐标来表示蛋白质结构的方法备受关注。通过将结构多样性归结为少数几个参数，此类方法可用于描绘可设计结构的空间，即能够被大量序列稳定的构象——这是从头蛋白质设计的一项关键任务。我们首先使用克里克参数化方法在天然α-螺旋卷曲螺旋上证明了这一点。我们表明，超过95%的已知卷曲螺旋结构与克里克理想主链的Cα均方根偏差在1 Å以内。推导得出的参数表明，卷曲螺旋的天然几何空间受到高度限制，并且可以由潜在连续构象中的“允许”构象来表示。允许的结构具有以下特点：1) 螺旋之间的轴向偏移受限，平行结构和反平行结构之间差异显著；2) 优选的超螺旋半径，其与寡聚化状态呈线性相关；3) 明显的依赖于半径的a和d位置氨基酸倾向；4) 螺旋绕其轴的离散旋转角度，令人惊讶的是，该角度与寡聚化状态或取向无关。总体而言，我们估计可设计的卷曲螺旋结构空间相对于几何上可行的结构空间至少减少了160倍。为了将结构参数化的优势扩展到其他系统，我们开发了一个用于对任意螺旋结构进行参数化的通用数学框架，该框架在特殊情况下可简化为克里克参数化。该方法在一组非卷曲螺旋螺旋束上得到了成功验证，这些螺旋束常见于通道和转运蛋白中，它们显示出明显的螺旋弯曲但没有超螺旋。卷曲螺旋参数拟合和结构生成程序可通过http://www.gevorggrigoryan.com/cccp/的网络界面获取，通用螺旋参数化的代码可应要求提供。
Because the space of folded protein structures is highly degenerate, with recurring secondary and tertiary motifs, methods for representing protein structure in terms of collective physically-relevant coordinates are of great interest. By collapsing structural diversity to a handful of parameters, such methods can be used to delineate the space of designable structures, i.e. conformations that can be stabilized with a large number of sequences – a crucial task for de novo protein design. We first demonstrate this on natural α-helical coiled coils using the Crick parameterization. We show that over 95% of known coiled-coil structures are within 1 Å Cα root mean square deviation of a Crick-ideal backbone. Derived parameters show that natural geometric space of coiled coils is highly restricted and can be represented by “allowed” conformations amidst a potential continuum of conformers. Allowed structures have 1) restricted axial offsets between helices, which differ starkly from parallel to anti-parallel structures; 2) preferred superhelical radii, which depend linearly on the oligomerization state; 3) pronounced radius-dependent a and d-position aminoacid propensities and 4) discrete angles of rotation of helices about their axes, which are surprisingly independent of oligomerization state or orientation. In all, we estimate the space of designable coiled-coil structures to be reduced at least 160-fold relative to the space of geometrically feasible structures. To extend the benefits of structural parameterization to other systems, we developed a general mathematical framework for parameterizing arbitrary helical structures, which reduces to the Crick parameterization as a special case. The method is successfully validated on a set of non coiled-coil helical bundles, frequent in channels and transporter proteins, which show significant helix bending but not supercoiling. Programs for coiled-coil parameter fitting and structure generation are provided via a web interface at http://www.gevorggrigoryan.com/cccp/, and code for generalized helical parameterization is available upon request.
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影响因子：
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作者：
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影响因子：
16.2
作者：
Howard, Rebecca J.;Clark, Kimberly A.;Minor, Daniel L., Jr.
通讯作者：
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影响因子：
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作者：
Grigoryan, G;Keating, AE
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0709068105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Hadley, Erik B.;Testa, Oliver D.;Gellman, Samuel H.
通讯作者：
Gellman, Samuel H.