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首页> 外文期刊>Journal of Molecular Biology >DETERMINATION OF THE DIFFERENTIAL EFFECTS OF HYDROGEN BONDING AND WATER RELEASE ON THE BINDING OF FK506 TO NATIVE AND TYR82-]PHE82 FKBP-12 PROTEINS USING FREE ENERGY SIMULATIONS
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DETERMINATION OF THE DIFFERENTIAL EFFECTS OF HYDROGEN BONDING AND WATER RELEASE ON THE BINDING OF FK506 TO NATIVE AND TYR82-]PHE82 FKBP-12 PROTEINS USING FREE ENERGY SIMULATIONS

机译：用自由能模拟确定氢键和水释放对FK506与天然和TYR82-] PHE82 FKBP-12蛋白质结合的不同作用

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摘要

We use the thermodynamic integration technique to calculate the free energy associated with the Tyr82 --> Phe82 mutation (Y82F) in the protein FKBP-12, both free and bound to known inhibitor FK506 (tacrolimis). We find that the net difference in free energy for the two changes is 0.85 kcal/mol, with the binding of FK506 relatively more favorable for the native protein than the mutant. This net energy compares very favorably with the experimentally measured value of 0.60 kcal/mol. The results indicate that the relatively better binding of FK506 to the native protein is driven by the favorable entropy associated with the release of water molecules from the protein when the ligand binds. For a variety of reasons, modest size of the system, smallness of the change being examined, rapid convergence of the ensemble that needs to be determined and use of statistical estimates to control sampling, we have been able to carry out atypically reliable and reproducible free energy calculations for this protein system. Free energy changes for the two simulations (Y82F FKBP-12/FK506 and Y82F FKBP-12) have been calculated a total of eight times each, to compare a variety of different methodological choices and to ensure that the results are statistically significant. Detailed analysis of the free energy results has been carried out, and indicates that even when applicable, deconvolution of the total free energy into components can be very difficult, that the statistical error estimates can give a reasonable bound on the error in a simulation, and that one must be careful to use the same simulation protocol in all simulations being compared. [References: 45]
机译：我们使用热力学积分技术来计算与蛋白FKBP-12中的Tyr82-> Phe82突变（Y82F）相关的自由能，该自由能既与已知抑制剂FK506（他克莫司）结合，又与之结合。我们发现，两个变化的自由能的净差为0.85 kcal / mol，与突变体相比，FK506对天然蛋白的结合相对更有利。该净能量与实验测量值0.60 kcal / mol相比非常有利。结果表明，当配体结合时，FK506与天然蛋白质的相对较好的结合是由与蛋白质释放水分子有关的有利熵驱动的。由于各种原因，系统的规模适中，正在研究的变更很小，需要确定的集合的快速收敛以及使用统计估计值来控制采样，我们已经能够进行非典型的可靠且可重复的生成该蛋白质系统的能量计算。两次模拟（Y82F FKBP-12 / FK506和Y82F FKBP-12）的自由能变化总计计算了八次，以比较各种不同的方法选择并确保结果具有统计学意义。对自由能的结果进行了详细的分析，结果表明，即使在适用的情况下，将总自由能反卷积为分量也可能非常困难，统计误差估计值可以对模拟中的误差给出合理的界限，并且必须比较小心地在所有模拟中使用相同的模拟协议。 [参考：45]

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