The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant
The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant
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DOI：
10.1021/ci3001919
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发表时间：
2012-08-01
影响因子：
5.6
通讯作者：
Ryde, Ulf
中科院分区：
文献类型：
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作者：
Genheden, Samuel;Kuhn, Oliver;Ryde, Ulf
我们对MM/GBSA（分子力学结合广义玻恩和表面积溶剂化）方法中的熵项进行了系统研究，以计算配体结合亲和力。熵是通过对分子动力学模拟的最小化快照的简谐频率进行正则模式分析来计算的。出于计算原因，这些计算通常在截断系统上进行。我们研究了八种凝血因子Xa抑制剂、九种铁蛋白配体和两种HIV - 1蛋白酶配体的结合情况，并表明去除距离配体大于8 - 16埃的蛋白质残基（包括4埃的固定蛋白质残基和水分子壳层），平均会使绝对熵改变1 - 5千焦/摩尔。然而，这种变化是系统性的，因此不同配体的相对熵平均仅改变0.7 - 1.6千焦/摩尔。因此，截断系统的熵所给出的相对结合亲和力在统计不确定性范围内（1 - 72千焦/摩尔）与整个蛋白质所获得的相同。我们还测试了在最小化和频率计算中使用与距离相关的介电常数（ε = 4r），但它通常会给出略有不同的熵和较差的结合亲和力。因此，我们建议使用最小截断半径（8埃）且ε = 1来计算熵。这种方法还能提高计算结合自由能的精度。
We have performed a systematic study of the entropy term in the MM/GBSA (molecular Mechanics combined with generalized Born and surface area solvation) approach to calculate ligand-binding affinities The entropies are calculated by a normal mode analysis of harmonic frequencies from minimized snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with. distances. larger than 8-16 angstrom to the ligand, including a 4 angstrom shell of fixed protein residues and water molecules, change the absolute entropies by 1-5 kJ/mol on average. However, the change is systematic, so relative entropies for different ligands change by only 0.7-1.6 kJ/mol on average. Consequently, entropies from truncated systems give relative binding affinities that are identical to those obtained for the Whole protein within statistical uncertainty (172 kJ/mol). We have also tested to use a distance dependent dielectric constant in the minimization and. frequency calculation (epsilon = 4r), but it typically gives slightly different entropies and poorer binding, affinities. Therefore, we recommend entropies calculated with the smallest truncation radius (8 angstrom) and epsilon =1 Such an approach also gives an improved precision for the calculated binding free energies.