Calculation of absolute protein-ligand binding affinity using path and endpoint approaches
Calculation of absolute protein-ligand binding affinity using path and endpoint approaches
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DOI：
10.1529/biophysj.105.071589
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发表时间：
2006-02-01
影响因子：
3.4
通讯作者：
Olson, MA
中科院分区：
文献类型：
--
作者：
Lee, MS;Olson, MA
比较分析了FKBP蛋白与小分子4-羟基-2-丁酮和FK506结合的两种蛋白质-配体复合体的绝对结合亲和力的精确和近似计算方法。我们的严格方法是伞状采样技术，其中平均作用力的势是通过在几个模拟窗口中将配体从蛋白质活性部位拉出来确定的。这种方法的结果与实验观察到的结合亲和力很好地吻合。还评估了一种常用的近似终点方法，该方法分别估计焓、溶剂化自由能和熵。我们表明，这种端点方法有许多变化，所有这些变化都容易出现严重的缺点。例如，对于这项工作中研究的相对简单的蛋白质-配体系统，传统的调和和准调和熵估计程序产生不同的结果。
A comparative analysis is provided of rigorous and approximate methods for calculating absolute binding affinities of two protein-ligand complexes: the FKBP protein bound with small molecules 4-hydroxy-2-butanone and FK506. Our rigorous approach is an umbrella sampling technique where a potential of mean force is determined by pulling the ligand out of the protein active site over several simulation windows. The results of this approach agree well with experimentally observed binding affinities. Also assessed is a commonly used approximate endpoint approach, which separately estimates enthalpy, solvation free energy, and entropy. We show that this endpoint approach has numerous variations, all of which are prone to critical shortcomings. For example, conventional harmonic and quasiharmonic entropy estimation procedures produce disparate results for the relatively simple protein-ligand systems studied in this work.