Exploring Local Molecular Docking through YASARA[1]
Andrew Michaelson
Northeastern University
April 9th, 2010
Instructor: Professor Mary Jo Ondrechen
Course: Molecular Modeling CHEM 5638
Using a modern molecular modeling software package such as YASARA[1] molecular docking of a
small molecule such as Quercetin to a protein such as Phosphoinositide 3-kinase can be achieved.
Molecular docking tries to find the best position that one molecule in our case Quercetin will bind
snuggly with a larger molecule in this case Phosphoinositide 3-kinase. Conformational changes that
result in an induced fit are found by reducing the minimum free energy of the complex formed by the
two molecules undergoing molecular docking. The minimum free energy is found by ΔG˚ = - RT log
Kd (this is labeled maximum binding energy in kcal/mol in Table 1). Phosphoinositide 3-kinase is an
important target for cancer since it mutated in cancer and this causes Phosphoinositide 3-kinase to be
more active as a result. Quercetin which is a known antioxidant can inhibit Phosphoinositide 3-kinase
to some extent; this is due to the small molecular size of the Quercetin which allows it to pass more
easily through the cell-membrane and the functional group of Quercetin which is the -OH group. Using
local molecular binding this report examines how mutating Quercetin can make it into a better inhibitor
of Phosphoinositide 3-kinase.
Figure 1 depicts the local docking pocket of the small molecule Quercetin with a 6 angstrom box
around the 4 residues Tryptophan 812, Lysine 883, Threonine 886, and Aspartate 964 (marked in
yellow) that make up the binding pocket of the active site in the molecule Phosphoinositide 3-Kinase.
In light blue the backbone using ball and stick modeling of the Phosphoinositide 3-Kinase can be seen,
in green the molecular surface of the Phosphoinositide 3-Kinase is shown.
Figure 2 depicts the small molecule Quercetin before mutation. The numbering of the carbon atoms of
the rings depict where in silico mutations were made (see Table 1 – Mutation at Site for specific
mutations). All atoms in this molecule are depicted using stick figures. Oxygen atoms are colored red,
Hydrogen atoms are colored white, and Carbon atoms are depicted in light blue.
In Table 1, there are 2 prominent runs where the maximum binding energy increased these 2 runs are
depicted in red (Run3 and Run6, see supplementary section for pictures). Run1 is the control where
Quercetin is run using local molecular docking without mutation (also shown in red). Table 1 also
shows global molecular docking using the same input files of Run1, Run2, and Run3 (see the
Supplementary Section* for more information). (The dissociation constants are not shown).
Examining Run3 which has 6 -OH groups a maximum binding energy of 8.09 kcal/mol and Run6
which has 11 -OH groups with a maximum binding energy of 10.04 kcal/mol in comparison with Run1
which only has 5 -OH groups and a binding energy of 7.65 kcal/mol, the Quercetin has a Maximum
Binding Energy which increases as more -OH groups are added to the Quercetin molecule. This
demonstrates that Quercetin can be a good inhibitor of Phosphoinositide 3-kinase. In addition Run2
and Run5 demonstrate what happens if no new -OH groups are added the maximum binding energy
actually stays the same as Run1 in this case. However, when -OH groups are removed as is the case in
Run4 the maximum binding energy actually is reduced to 5.64 kcal/mol. In conclusion this
demonstrates that mutating the small molecule Quercetin can decrease the activity of Phosphoinositide
3-kinase if more -OH groups are added to Quercetin.
Supplementary Section*
In Table 1, 3 global molecular dockings were done to see if other sites could be found where the
maximum binding energy might increase for a local molecular docking. However it is beyond the scope
of this report to examine where the results of this question can lead. Though it would be interesting to
find another even better local docking site as a result.
The protocol for setting up the global molecular docking was as follows:
1. Create a project directory called 'mydirectory'.
2. Save a copy of the scene complex file of any of the local docking molecular docking files in
complex before simulation of local docking into 'mydirectory'.
3. Save a copy of your ligand titled in this format, specifically in this case 'PI3Kque1_ligand.pdb'
into 'mydirectory'.
4. Save a copy of your receptor titled in this format, specifically in this case
'PI3Kque1_receptor.pdb' into 'mydirectory'.
5. Under Options go to Macro & Movie and click Set Target choose 'mydirectory' and leave out
the extension name (this is the same as what is done in local molecular docking).
6. Under Options go to Macro & Movie and click Play Macro in the Yasara folder entitled 'mcr'
click on the macro 'dock_run.mcr'.
7. If simulation asks to reset size of cell in my case I used 5.0 angstroms around all atoms for all
global molecular dockings. This can be done by clicking under Simulation, Define simulation
cell and clicking Extend '5.0' angstroms and then clicking on 'around all atoms'.
8. Finally examine the log file in 'mydirectory' created to determine how well the global molecular
docking went.
References:
1. YASARA Biosciences (2007) YASARA: Yet another scientific artificial reality application. Available:
http://www.yasara.org/. Accessed 02 February 2010.
2. Morris, G., D. Goodsell, R. Halliday, R. Huey, W. Hart, R. Belew, and A. Olson, Automated Docking
Using a Lamarckian Genetic Algorithm and Empirical Binding Free Energy Function J Comput Chem,
1998. 19: p. 1639-1662.
3. Stephens, L., R. Williams, and P. Hawkins, Phosphoinositide 3-kinases as drug targets in cancer.
Current Opinion in Pharmacology, 2005. 5: p. 357-365.
4. Walker, E., M. Pacold, O. Perisic, L. Stephens, P. Hawkins, M. Wymann, and R. Williams, Structural
determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin,
and staurosporine. Mol Cell, 2000. 6: p. 909-919.