Journal
JOURNAL OF COMPUTATIONAL CHEMISTRY
Volume 26, Issue 9, Pages 915-931Publisher
WILEY
DOI: 10.1002/jcc.20222
Keywords
protein docking; DFT; QM/MM; lead optimization
Categories
Funding
- NIGMS NIH HHS [R01 GM040526, GM43340, GM 40526, R01 GM043340] Funding Source: Medline
Ask authors/readers for more resources
The extent to which accuracy of electric charges plays a role in protein-ligand docking is investigated through development of a docking algorithm, which incorporates quantum mechanical/molecular mechanical (QM/MM) calculations. In this algorithm, fixed charges of ligands obtained from force field parameterization are replaced by QM/MM calculations in the protein environment, treating only the ligands as the quantum region. The algorithm is tested on a set of 40 cocrystallized structures taken from the Protein Data Bank (PDB) and provides strong evidence that use of nonfixed charges is important. An algorithm, dubbed Survival of the Fittest (SOF) algorithm, is implemented to incorporate QM/MM charge calculations without any prior knowledge of native structures of the complexes. Using an iterative protocol, this algorithm is able in many cases to converge to a nativelike structure in systems where redocking of the ligand using a standard fixed charge force field exhibits nontrivial errors. The results demonstrate that polarization effects can play a significant role in determining the structures of protein-ligand complexes, and provide a promising start towards the development of more accurate docking methods for lead optimization applications. (c) 2005 Wiley Periodicals, Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available