Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Validation of ligands in X-ray crystal structures

As of late 2014, the Protein Data Bank (PDB) contained over 105,000 structures, of which over 26,000 X-ray crystal structures contained at least one of >18,000 organic ligand molecules. The number of ligand:protein structures in the PDB is growing rapidly considering that over 10,000 structures were deposited in last five years. Current structure refinement and validation protocols are well suited for biomolecular structures like proteins and nucleic acids, but are far from optimal for non-covalently bound ligands in such structures. The undetected errors and uncertainty in the ligand:protein structures can lead to the misinterpretation of experimental data and possible failure of drug discovery efforts.


I will present case studies on the applications of molecular dynamics simulations and free energy calculations in conjunction with well-validated ligand force field parameters in validating and correcting the structure and binding pose(s) of ligands in X-ray crystal structures.

    Koziara, K. C., Stroet, M., Malde, A. K. & Mark, A. E. (2014). Testing and validation of the Automated Topology Builder (ATB) version 2.0: Prediction of hydration free enthalpies. Journal of Computer-Aided Molecular Design 28, 221-233.

    Nair, P. C., Malde, A. K., Drinkwater, N. & Mark, A. E. (2012). Missing Fragments: Detecting cooperative binding in fragment based drug design. ACS Medicinal Chemistry Letters 3, 322-326. Malde, A. K. & Mark, A. E. (2011). Challenges in determining the binding modes of non-standard ligands in X-ray crystal complexes. Journal of Computer-Aided Molecular Design 25, 1-12.

    Malde, A. K., Zuo, L., Breeze, M., Stroet, M., Poger, D., Nair, P. C., Oostenbrink, C., & Mark, A. E. (2011). An Automated force field Topology Builder (ATB) and repository: version 1.0. Journal of Chemical Theory and Computation 7, 4026-4037.

Alpeshkumar K. Malde*
Alan E. Mark

School of Chemistry
Molecular Biosciences
University of Queensland
Brisbane, QLD 4072, Australia

Ph: +61 7 3365 7562
Fx: +61 7 3365 3872