Alternate states of proteins revealed by detailed energy landscape mapping.
Alternate states of proteins revealed by detailed energy landscape mapping.
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DOI：
10.1016/j.jmb.2010.11.008
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发表时间：
2011-01-14
影响因子：
5.6
通讯作者：
Baker D
中科院分区：
文献类型：
--
作者：
Tyka MD;Keedy DA;André I;Dimaio F;Song Y;Richardson DC;Richardson JS;Baker D
蛋白质分子在溶液中的构象是什么？晶体学提供了晶体环境中蛋白质结构的高分辨率描述，而NMR描述了溶液中的结构，但使用的数据较少。核磁共振结构显示出更多的可变性，但这是因为晶体接触不存在还是因为数据约束较少？在这里，我们报告了对这个问题的意想不到的见解，通过分析由Rosetta@HOME对111个蛋白质结构域的构象空间进行大规模天然增强采样所产生的详细蛋白质能量景观。在没有紧密结合的结合配偶体或配体的情况下，最低能量的Rosetta模型几乎都小于2.5 μ CαRMSD;这一结果表明，球状蛋白质的结构预测准确性主要受到接近天然结构的采样能力的限制。虽然最低能量模型与沉积结构相似，但它们并不相同;最大的偏差通常发生在配体、四元或晶体接触的区域。对于配体结合蛋白，低能量模型可能类似于载脂蛋白结构，而对于寡聚蛋白，则类似于单体组装中间体。当在晶格或多聚体的背景下计算景观时，低能模型和晶体结构之间的偏差基本上消失了。计算的低能量合奏，紧密的晶体结构，如包装的核心，但更多的NMR结构的变化，在循环中，可能在某些情况下类似于天然状态合奏的蛋白质比个别晶体或NMR结构，并可以建议实验可检验的假设有关的替代状态和结构异质性的功能。
What conformations do protein molecules populate in solution? Crystallography provides a high-resolution description of protein structure in the crystal environment, while NMR describes structure in solution but using less data. NMR structures display more variability, but is this because crystal contacts are absent or because of fewer data constraints? Here we report unexpected insight into this issue obtained through analysis of detailed protein energy landscapes generated by large-scale, native-enhanced sampling of conformational space with Rosetta@HOME for 111 protein domains. In the absence of tightly associating binding partners or ligands, the lowest-energy Rosetta models were nearly all <2.5Å CαRMSD from the experimental structure; this result demonstrates that structure prediction accuracy for globular proteins is limited mainly by the ability to sample close to the native structure. While the lowest-energy models are similar to deposited structures, they are not identical; the largest deviations are most often in regions involved in ligand, quaternary, or crystal contacts. For ligand binding proteins, the low energy models may resemble the apo structures, and for oligomeric proteins, the monomeric assembly intermediates. The deviations between the low energy models and crystal structures largely disappear when landscapes are computed in the context of the crystal lattice or multimer. The computed low-energy ensembles, with tight crystal-structure-like packing in the core, but more NMR-structure-like variability in loops, may in some cases resemble the native state ensembles of proteins better than individual crystal or NMR structures, and can suggest experimentally testable hypotheses relating alternative states and structural heterogeneity to function.
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影响因子：
5.6
作者：
Eyal, E;Gerzon, S;Sobolev, V
通讯作者：
Sobolev, V
影响因子：
5.7
作者：
Levin, Elena J.;Kondrashov, Dmitry A.;Phillips, George N., Jr.
通讯作者：
Phillips, George N., Jr.
DOI：
10.1073/pnas.0800256105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Shen, Yang;Lange, Oliver;Bax, Ad
通讯作者：
Bax, Ad
影响因子：
2.9
作者：
Das, Rhiju;Bin Qian;Baker, David
通讯作者：
Baker, David
影响因子：
2.9
作者：
Keedy, Daniel A.;Williams, Christopher J.;Richardson, Jane S.
通讯作者：
Richardson, Jane S.