On the Use of Molecular Dynamics Receptor Conformations for Virtual Screening
Receptors are inherently dynamic and this flexibility is important to consider when constructing a model of molecular association. Conformations from molecular dynamics simulations, a well-established method for examining protein dynamics, can be used in virtual screening to account for flexibility in structure-based drug discovery. Different receptor configurations influence docking results. Molecular dynamics simulations can provide snapshots that improve virtual screening predictive power over known crystal structures, most likely as a result of sampling more relevant receptor conformations. Here we highlight some details and nuances of using such snapshots and evaluating them for predictive performance.
Key wordsDocking Receptor structures X-ray crystallography Molecular dynamics
The authors would like to thank the members of the McCammon research group for useful discussions. This work was supported in part by the National Science Foundation, the National Institutes of Health, Howard Hughes Medical Institute, the San Diego Supercomputer Center, the Center for Theoretical Biological Physics and the National Biomedical Computational Resource.
- 1.Wu, B., Chien, E., Mol, C., Fenalti, G., Liu, W., Katritch, V., Abagyan, R., Brooun, A., Wells, P., Bi, F., Hamel, D., Kuhn, P., Handel, T., Cherezov, V., and Stevens, R. (2010) Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists, Science 330, 1066–1071.Google Scholar
- 4.Meiler, J., and Baker, D. (2006) ROSETTALIGAND: Protein-small molecule docking with full side-chain flexibility, Proteins 65, 538–548.Google Scholar
- 5.Morris, G., Huey, R., Lindstrom, W., Sanner, M., Belew, R., Goodsell, D., and Olson, A. (2009) AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility, J Comput Chem 30, 2785–2791.Google Scholar
- 9.Nichols, S. E., Baron, R., and McCammon, J. A. (2011) Predictive Power of Molecular Dynamics Receptor Structures in Virtual Screening, J Chem Info Model 51, 1439–1446.Google Scholar
- 15.Nichols, S., Domaoal, R., Thakur, V., Tirado-Rives, J., Anderson, K., and Jorgensen, W. (2009) Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures., J Chem Info Model 49, 1272–1279.CrossRefGoogle Scholar