Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding
Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding
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DOI：
10.1021/jm060763i
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发表时间：
2006-10-05
影响因子：
7.3
通讯作者：
Jorgensen, William L.
中科院分区：
文献类型：
--
作者：
Tirado-Rives, Julian;Jorgensen, William L.
当配体与蛋白质结合时，它通常不是处于未结合配体的最低能量构象中，并且构象自由度也会丧失。本文正式讨论了这种“构象聚焦”的自由能变化，并在蛋白质与配体对接的评分函数和绝对结合自由能的计算中考虑了其估计或忽略的相关误差。报道了抑制HIV-1逆转录酶的具体应用。结论是，仅这一来源的不确定性就足以排除当前对接方法在高通量虚拟筛选中对不同化合物进行排序的可行性。
When a ligand binds to a protein, it is typically not in the lowest-energy conformation for the unbound ligand and there is also a loss of conformational degrees of freedom. The free-energy change for this "conformer focusing" is addressed here formally, and the associated errors with its estimation or neglect are considered in the context of scoring functions for protein-ligand docking and computation of absolute free energies of binding. Specific applications for inhibition of HIV-1 reverse transcriptase are reported. It is concluded that the uncertainties from this source alone are sufficient to preclude the viability of current docking methodology for rank-ordering of diverse compounds in high-throughput virtual screening.