Protein/ligand binding free energies calculated with quantum mechanics/molecular mechanics

被引:91
作者
Gräter, F
Schwarzl, SM
Dejaegere, A
Fischer, S
Smith, JC
机构
[1] Heidelberg Univ, IWR Computat Biochem, D-69120 Heidelberg, Germany
[2] Heidelberg Univ, IWR Computat Mol Biophys, D-69120 Heidelberg, Germany
[3] Ecole Super Biotechnol Strasbourg, UMR 7104, Dept Biol Genom Struct, FR-67400 Illkirch Graffenstaden, France
关键词
D O I
10.1021/jp044185y
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
The calculation of binding affinities for flexible ligands has hitherto required the availability of reliable molecular mechanics parameters for the ligands, a restriction that can in principle be lifted by using a mixed quantum mechanics/molecular mechanics (QM/MM) representation in which the ligand is treated quantum mechanically. The feasibility of this approach is evaluated here, combining QM/MM with the Poisson-Boltzmann/surface area model of continuum solvation and testing the method on a set of 47 benzamidine derivatives binding to trypsin. The experimental range of the absolute binding energy (Delta G = -3.9 to -7.6 kcal/mol) is reproduced well, with a root- mean-square (RMS) error of 1.2 kcal/mol. When QM/MM is applied without reoptimization to the very different ligands of FK506 binding protein the RMS error is only 0.7 kcal/mol. The results show that QM/MM is a promising new avenue for automated docking and scoring of flexible ligands. Suggestions are made for further improvements in accuracy.
引用
收藏
页码:10474 / 10483
页数:10
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