Full protein flexibility is essential for proper hot-spot mapping.
Full protein flexibility is essential for proper hot-spot mapping.
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DOI：
10.1021/ja1079332
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发表时间：
2011-01-19
影响因子：
15
通讯作者：
Carlson HA
中科院分区：
文献类型：
--
作者：
Lexa KW;Carlson HA
A traditional technique for structure-based drug design (SBDD) is mapping protein surfaces with probe molecules to identify “hot spots” where key functional groups can best complement the receptor. Common methods, such as minimizing probes or calculating grids, use a fixed protein structure in the gas phase, ignoring both protein flexibility and proper competition between the probes and water. As a result, the potential surface is quite rugged and many spurious, local minima are identified. Here, we compare rigid and fully flexible protein in mixed-solvent molecular dynamics (MixMD), which allows for flexibility and full solvent effects. We were surprised to find that that the many local minima are still found when a protein's conformational sampling is restricted; the dynamic averaging of probes and competition with water does not smooth the potential surface as one might expect. Only when a protein is allowed to be fully flexible in the simulation are the proper minima located and the spurious ones eliminated. Our results indicate that inclusion of full protein flexibility is critical to accurate hot-spot mapping for SBDD.
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影响因子：
3
作者：
Landon, Melissa R.;Amaro, Rommie E.;Baron, Riccardo;Ngan, Chi Ho;Ozonoff, David;McCammon, J. Andrew;Vajda, Sandor
通讯作者：
Vajda, Sandor
DOI：
10.1073/pnas.062398499
发表时间：
2002-04-02
影响因子：
11.1
作者：
Dennis, S;Kortvelyesi, T;Vajda, S
通讯作者：
Vajda, S
影响因子：
15
作者：
Meagher, KL;Carlson, HA
通讯作者：
Carlson, HA
影响因子：
7.3
作者：
GOODFORD, PJ
通讯作者：
GOODFORD, PJ
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML