A Pareto-optimal refinement method for protein design scaffolds.
A Pareto-optimal refinement method for protein design scaffolds.
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DOI：
10.1371/journal.pone.0059004
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Baker D
中科院分区：
文献类型：
--
作者：
Nivón LG;Moretti R;Baker D
蛋白质功能的计算设计涉及寻找具有最低能量的氨基酸，并受到一组指定功能的约束。在许多情况下，搜索一组天然蛋白质主链结构或“支架”以找到可以放置功能位点（酶活性位点、配体结合袋、蛋白质-蛋白质相互作用区域等）的区域，并且优化周围氨基酸的特性以满足功能限制。输入的天然蛋白质结构几乎总是具有在设计力场中得分非常差的区域，并且任何基于这些未修饰结构的设计都可能仅由于能量应变而导致远离天然序列的突变。由于输入结构已经是稳定的蛋白质，因此需要将突变总数保持在最低限度，并避免由得分不佳的输入结构导致的突变。在这里，我们描述了一种使用最小化循环并结合主链/侧链约束的协议，该协议在原生结构的 RMSD 和能量应变减少方面是帕累托最优的。该协议应该广泛用于准备功能位点设计的脚手架库。
Computational design of protein function involves a search for amino acids with the lowest energy subject to a set of constraints specifying function. In many cases a set of natural protein backbone structures, or “scaffolds”, are searched to find regions where functional sites (an enzyme active site, ligand binding pocket, protein – protein interaction region, etc.) can be placed, and the identities of the surrounding amino acids are optimized to satisfy functional constraints. Input native protein structures almost invariably have regions that score very poorly with the design force field, and any design based on these unmodified structures may result in mutations away from the native sequence solely as a result of the energetic strain. Because the input structure is already a stable protein, it is desirable to keep the total number of mutations to a minimum and to avoid mutations resulting from poorly-scoring input structures. Here we describe a protocol using cycles of minimization with combined backbone/sidechain restraints that is Pareto-optimal with respect to RMSD to the native structure and energetic strain reduction. The protocol should be broadly useful in the preparation of scaffold libraries for functional site design.
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影响因子：
64.8
作者：
DiMaio, Frank;Terwilliger, Thomas C.;Read, Randy J.;Wlodawer, Alexander;Oberdorfer, Gustav;Wagner, Ulrike;Valkov, Eugene;Alon, Assaf;Fass, Deborah;Axelrod, Herbert L.;Das, Debanu;Vorobiev, Sergey M.;Iwai, Hideo;Pokkuluri, P. Raj;Baker, David
通讯作者：
Baker, David
影响因子：
5.6
作者：
Gray, JJ;Moughon, S;Baker, D
通讯作者：
Baker, D
影响因子：
5.6
作者：
Tyka MD;Keedy DA;André I;Dimaio F;Song Y;Richardson DC;Richardson JS;Baker D
通讯作者：
Baker D
DOI：
10.1126/science.1202617
发表时间：
2011-05-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fleishman SJ;Whitehead TA;Ekiert DC;Dreyfus C;Corn JE;Strauch EM;Wilson IA;Baker D
通讯作者：
Baker D
影响因子：
56.9
作者：
Kuhlman, B;Dantas, G;Baker, D
通讯作者：
Baker, D