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Application of a polarizable force field to calculations of relative protein-ligand binding affinities.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2008 Jul 29; Vol. 105 (30), pp. 10378-83. Date of Electronic Publication: 2008 Jul 24. - Publication Year :
- 2008
-
Abstract
- An explicitly polarizable force field based exclusively on quantum data is applied to calculations of relative binding affinities of ligands to proteins. Five ligands, differing by replacement of an atom or functional group, in complexes with three serine proteases-trypsin, thrombin, and urokinase-type plasminogen activator-with available experimental binding data are used as test systems. A special protocol of thermodynamic integration was developed and used to provide sufficiently low levels of systematic error along with high numerical efficiency and statistical stability. The calculated results are in excellent quantitative (rmsd = 1.0 kcal/mol) and qualitative (R(2) = 0.90) agreement with experimental data. The potential of the methodology to explain the observed differences in the ligand affinities is also demonstrated.
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 105
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 18653760
- Full Text :
- https://doi.org/10.1073/pnas.0803847105