Conformational energy penalties of protein-bound ligands
Conformational energy penalties of protein-bound ligands
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DOI：
10.1023/a:1008007507641
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发表时间：
1998-07-01
影响因子：
3.5
通讯作者：
Liljefors, T
中科院分区：
文献类型：
--
作者：
Bostrom, J;Norrby, PO;Liljefors, T
计算了33种配体-蛋白质复合物（包括28种不同的配体）的配体构象所需的构象能。为了监测结果的力场依赖性，采用两个力场MM 3 * 和AMBER* 进行计算。采用广义Born/溶剂可及表面（GB/SA）溶剂化模型，在真空和水溶液中进行构象分析。通过使用平底笛卡尔约束来放松蛋白质结合构象。对于所研究的约70%的配体-蛋白质复合物，生物活性构象的构象能被计算为小于或等于3 kcal/mol。它表明，在这种类型的计算中，未结合的配体的水溶液构象合奏必须用作参考状态。配体-蛋白质复合物的计算与计算的配体的构象能罚大于3千卡/摩尔遭受的实验数据的解释或计算方法的局限性的不确定性。例如，在长链柔性配体（例如，脂肪酸）的情况下，它表明，可以发现几种构象是非常相似的X射线晶体学确定的构象，并显示显着较低的构象能量罚款的结合比通过使用实验构象。对于强极性分子，如氨基酸，结果表明，进一步发展的力场和介电连续溶剂化模型是需要可靠的计算这类化合物的构象特性。
The conformational energies required for ligands to adopt their bioactive conformations were calculated for 33 ligand-protein complexes including 28 different ligands. In order to monitor the force field dependence of the results, two force fields, MM3* and AMBER*, were employed for the calculations. Conformational analyses were performed in vacuo and in aqueous solution by using the generalized Born/solvent accessible surface (GB/SA) solvation model. The protein-bound conformations were relaxed by using flat-bottomed Cartesian constraints. For about 70% of the ligand-protein complexes studied, the conformational energies of the bioactive conformations were calculated to be less than or equal to 3 kcal/mol. It is demonstrated that the aqueous conformational ensemble for the unbound ligand must be used as a reference state in this type of calculations. The calculations for the ligand-protein complexes with conformational energy penalties of the ligand calculated to be larger than 3 kcal/mol suffer from uncertainties in the interpretation of the experimental data or limitations of the computational methods. For example, in the case of long-chain flexible ligands (e.g, fatty acids), it is demonstrated that several conformations may be found which are very similar to the conformation determined by X-ray crystallography and which display significantly lower conformational energy penalties for binding than obtained by using the experimental conformation. For strongly polar molecules, e.g. amino acids, the results indicate that further developments of the force fields and of the dielectric continuum solvation model are required for reliable calculations on the conformational properties of this type of compounds.