Conformational energy range of ligands in protein crystal structures: The difficult quest for accurate understanding.
Conformational energy range of ligands in protein crystal structures: The difficult quest for accurate understanding.
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DOI：
10.1002/jmr.2618
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Nicklaus MC
中科院分区：
文献类型：
--
作者：
Peach ML;Cachau RE;Nicklaus MC
在这篇综述中，我们解决了一个基本问题：在蛋白质-配体晶体结构中，配体的构象能的范围是什么？这个值对于更好地理解蛋白质-配体结合过程具有重要的生物物理学意义；在实践中，为对接和药效团搜索等许多计算药物设计方法提供了一个参数。我们综合了先前报道的关于这个问题的计算研究中相互矛盾的结果，并得出结论，高配体构象能确实存在于某些晶体结构中。不同分析之间分歧的主要来源似乎是由于对静电和溶剂化的不同处理。然而，与此同时，对于许多配体来说，由于晶体结构的不精确或参考态的不正确确定，高构象能是错误的。除了简单的化学错误外，我们认为晶体结构错误可能主要是由于配体立体化学约束相对于结构与电子密度的拟合的启发式加权。这个问题不能通过改进电子密度拟合或简单的配体几何检查来解决，尽管在结构改进过程中除了几何外，还需要更好的指标来评估配体和结合位点化学。精确确定配体构象能的最终解决方案在于超高分辨率的晶体结构，可以不受限制地进行细化。在蛋白质-配体晶体结构中，配体的构象能的范围是多少？我们综合了前人对这一问题的计算研究结果，得出了在某些晶体结构中存在高能量的结论，而误差主要是由于配体立体化学约束的权重相对于结构与电子密度的拟合。精确测定配体构象能的解决方案是可以不受限制地细化的超高分辨率晶体结构。
In this review we address a fundamental question: what is the range of conformational energies seen in ligands in protein-ligand crystal structures? This value is important biophysically, for better understanding the protein-ligand binding process; and practically, for providing a parameter to be used in many computational drug design methods such as docking and pharmacophore searches. We synthesize a selection of previously reported conflicting results from computational studies of this issue, and conclude that high ligand conformational energies really are present in some crystal structures. The main source of disagreement between different analyses appears to be due to divergent treatments of electrostatics and solvation. At the same time, however, for many ligands a high conformational energy is in error, due to either crystal structure inaccuracies or incorrect determination of the reference state. Aside from simple chemistry mistakes, we argue that crystal structure error may mainly be due to the heuristic weighting of ligand stereochemical restraints relative to the fit of the structure to the electron density. This problem cannot be fixed with improvements to electron density fitting or with simple ligand geometry checks, though better metrics are needed for evaluating ligand and binding site chemistry in addition to geometry during structure refinement. The ultimate solution for accurately determining ligand conformational energies lies in ultra-high resolution crystal structures that can be refined without restraints. What is the range of conformational energies seen in ligands in protein-ligand crystal structures? We synthesize results from previous computational studies of this issue and conclude that high energies are present in some crystal structures, whereas errors are mainly due to the weighting of ligand stereochemical restraints relative to structure fitting into the electron density. The solution for accurately determining ligand conformational energies is ultra-high resolution crystal structures which can be refined without restraints.
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影响因子：
8.6
作者：
Cereto-Massagué A;Ojeda MJ;Joosten RP;Valls C;Mulero M;Salvado MJ;Arola-Arnal A;Arola L;Garcia-Vallvé S;Pujadas G
通讯作者：
Pujadas G
DOI：
10.1107/s0907444906012601
发表时间：
2006-06-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Danley, Dennis E.
通讯作者：
Danley, Dennis E.
影响因子：
5.7
作者：
Adams, Paul D.;Aertgeerts, Kathleen;Bauer, Cary;Bell, Jeffrey A.;Berman, Helen M.;Bhat, Talapady N.;Blaney, Jeff M.;Bolton, Evan;Bricogne, Gerard;Brown, David;Burley, Stephen K.;Case, David A.;Clark, Kirk L.;Darden, Tom;Emsley, Paul;Feher, Victoria A.;Feng, Zukang;Groom, Colin R.;Harris, Seth F.;Hendle, Jorg;Holder, Thomas;Joachimiak, Andrzej;Kleywegt, Gerard J.;Krojer, Tobias;Marcotrigiano, Joseph;Mark, Alan E.;Markley, John L.;Miller, Matthew;Minor, Wladek;Montelione, Gaetano T.;Murshudov, Garib;Nakagawa, Atsushi;Nakamura, Haruki;Nicholls, Anthony;Nicklaus, Marc;Nolte, Robert T.;Padyana, Anil K.;Peishoff, Catherine E.;Pieniazek, Susan;Read, Randy J.;Shao, Chenghua;Sheriff, Steven;Smart, Oliver;Soisson, Stephen;Spurlino, John;Stouch, Terry;Svobodova, Radka;Tempel, Wolfram;Terwilliger, Thomas C.;Tronrud, Dale;Velankar, Sameer;Ward, Suzanna C.;Warren, Gregory L.;Westbrook, John D.;Williams, Pamela;Yang, Huanwang;Young, Jasmine
通讯作者：
Young, Jasmine
DOI：
10.1107/s0907444907046148
发表时间：
2007-11
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Afonine PV;Grosse-Kunstleve RW;Adams PD;Lunin VY;Urzhumtsev A
通讯作者：
Urzhumtsev A
影响因子：
7.3
作者：
ANDREWS, PR;CRAIK, DJ;MARTIN, JL
通讯作者：
MARTIN, JL