Summary
A genetic algorithm (GA) based method for docking ensembles of small, flexible ligands to receptor proteins using NMR-derived constraints is described. In this method, three translations and rotations of the ligand and the dihedral angles of the ligand are represented by binary strings and evolve under the genetic operators of cross-over, mutation, migration and selection. The fitness function for the selection process includes distance and dihedral restraints and a repulsive van der Waals term. The GA was applied to a three-atom model system as well as to the streptavidin-biotin complex using simulated intermolecular distance restraints. In both systems, the GA was able to obtain low-energy conformations when only a single binding site was simulated. Calculations were also performed using distance restraints from two distinct binding sites. In these simulations, the GA was able to obtain low-energy conformations corresponding to ligand molecules in each of the two sites. The inclusion of additional ligands in the ensemble did not result in an energetic benefit, confirming that only two ligand conformations were necessary to fulfill the distance restraints. This method allows for a direct investigation of the minimum number of ligand orientations necessary to fulfill experimental distance restraints, and simultaneously yields detailed structural information about each site.
Similar content being viewed by others
References
BrodmeierT. and PretschE. (1994) J. Comput. Chem., 15, 588–595.
DandekarT. and ArgosP. (1994) J. Mol. Biol., 236, 844–861.
ForrestS. (1993) Science, 261, 872–878.
GoldbergD.E. (1989) Genetic Algorithms in Search, Optimization, and Machine Learning, Addison-Wesley, New York, NY.
HavenT.F. and WüthrichK. (1984) Bull. Math. Biol., 46, 675–698.
HollandJ.H. (1992) Adaptation in Natural and Artificial Systems, MIT Press, Cambridge, MA.
JudsonR.S., JaegerE.P., TreasurywalaA.M. and PetersonM.L. (1993) J. Comput. Chem., 14, 1407–1414.
McGarrahD.B. and JudsonR.S. (1993) J. Comput. Chem., 14, 1385–1395.
MierkeD.F., KurzM. and KesslerH. (1994) J. Am. Chem. Soc., 116, 1042–1049.
NilgesM., CloreG.M. and GronenbornA.M. (1988) FEBS Lett., 239, 129–136.
SchafferJ.D. (Ed.) (1989) Proceedings of the Third International Conference on Genetic Algorithms, Morgan Kaufmann, San Mateo, CA.
SchmitzU., UlyanovN.B., KumarA. and JamesT.L. (1993) J. Mol. Biol., 234, 373–389.
TordaA.E., ScheekR.M. and VanGunsterenW.F. (1989) Chem. Phys. Lett., 157, 289–294.
WeberP.C., OhlendorfD.H., WendoloskiJ.J. and SalammeF.R. (1989) Science, 243, 85–88.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Meadows, R.P., Hajduk, P.J. A genetic algorithm-based protocol for docking ensembles of small ligands using experimental restraints. J Biomol NMR 6, 41–47 (1995). https://doi.org/10.1007/BF00417490
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00417490