531
15 (How to) Profit from Molecular Dynamics-based Ensemble Docking
Besides the expected methodological improvements the high-throughput application of the ensemble docking becomes more and more realistic with continuously
increasing computational resources. With the current computational power and the
efficient use of GPU facilities for simulation, the time for the generation of an MD
ensemble will no longer be a limit for the its application for subsequent docking.
These circumstances will also enforce the use of computationally more demanding
methods which are more accurate than docking scores and ensemble docking might
be facing a competition with free energy estimation techniques inherently including flexibility aspects. Nevertheless, the potential benefit of a defined workflow for
virtual screening based on an MD-derived ensemble as strategy including target
flexibility is evident. MD-based ensemble docking has the potential to become a
standard procedure particularly for detection of chemically different ligands within
next decades.
Acknowledgments Presented work was supported by funding of the Austrian Science Fund
FWF: project “Targeting Influenza Neuraminidase” (P23051). Julian E. Fuchs is a recipient of a
DOC-fellowship of the Austrian Academy of Sciences at the Institute of General, Inorganic and
Theoretical Chemistry at University of Innsbruck.
References
1. Boehr DD, McElheny D, Dyson HJ, Wright PE (2006) The dynamic energy landscape of dihydrofolate reductase catalysis. Science 313(5793):1638–1642. doi:10.1126/science.1130258
2. Fischer E (1894) Einfluss der Configuration auf die Wirkung der Enzyme. Ber Dtsch Chem
Ges 27
3. Koshland DE (1958) Application of a theory of enzyme specificity to protein synthesis. Proc
Natl Acad Sci U S A 44 98–104
4. Tsai CJ, Ma BY, Nussinov R (1999) Folding and binding cascades: shifts in energy landscapes. Proc Natl Acad Sci U S A 96(18):9970–9972. doi:10.1073/pnas.96.18.9970
5. Tsai CJ, Kumar S, Ma BY, Nussinov R (1999) Folding funnels, binding funnels, and protein
function. Protein Sci 8(6):1181–1190
6. Boehr DD, Nussinov R, Wright PE (2009) The role of dynamic conformational ensembles in
biomolecular recognition. Nat Chem Biol 5(11):789–796. doi:10.1038/nchembio.232
7. Durrant JD, McCammon JA (2010) Computer-aided drug-discovery techniques that account
for receptor flexibility. Curr Opin Pharmacol 10(6):770–774. doi:10.1016/j.coph.2010.09.001
8. Totrov M, Abagyan R (2008) Flexible ligand docking to multiple receptor conformations: a
practical alternative. Curr Opin Struct Biol 18(2):178–184. doi:10.1016/j.sbi.2008.01.004
9. Carlson HA, McCammon JA (2000) Accommodating protein flexibility in computational
drug design. Mol Pharmacol 57(2):213–218
10. Carlson HA (2002) Protein flexibility is an important component of structure-based drug
discovery. Curr Pharm Des 8(17):1571–1578. doi:10.2174/1381612023394232
11. Chaudhury S, Gray JJ (2008) Conformer selection and induced fit in flexible backbone protein-protein docking using computational and NMR ensembles. J Mol Biol 381(4):1068–
1087. doi:10.1016/j.jmb.2008.05.042
12. Henzler-Wildman KA, Lei M, Thai V, Kerns SJ, Karplus M, Kern D (2007) A hierarchy of
timescales in protein dynamics is linked to enzyme catalysis. Nature 450(7171):913–U27.
doi:10.1038/nature06407
15 (How to) Profit from Molecular Dynamics-based Ensemble Docking
Besides the expected methodological improvements the high-throughput application of the ensemble docking becomes more and more realistic with continuously
increasing computational resources. With the current computational power and the
efficient use of GPU facilities for simulation, the time for the generation of an MD
ensemble will no longer be a limit for the its application for subsequent docking.
These circumstances will also enforce the use of computationally more demanding
methods which are more accurate than docking scores and ensemble docking might
be facing a competition with free energy estimation techniques inherently including flexibility aspects. Nevertheless, the potential benefit of a defined workflow for
virtual screening based on an MD-derived ensemble as strategy including target
flexibility is evident. MD-based ensemble docking has the potential to become a
standard procedure particularly for detection of chemically different ligands within
next decades.
Acknowledgments Presented work was supported by funding of the Austrian Science Fund
FWF: project “Targeting Influenza Neuraminidase” (P23051). Julian E. Fuchs is a recipient of a
DOC-fellowship of the Austrian Academy of Sciences at the Institute of General, Inorganic and
Theoretical Chemistry at University of Innsbruck.
References
1. Boehr DD, McElheny D, Dyson HJ, Wright PE (2006) The dynamic energy landscape of dihydrofolate reductase catalysis. Science 313(5793):1638–1642. doi:10.1126/science.1130258
2. Fischer E (1894) Einfluss der Configuration auf die Wirkung der Enzyme. Ber Dtsch Chem
Ges 27
3. Koshland DE (1958) Application of a theory of enzyme specificity to protein synthesis. Proc
Natl Acad Sci U S A 44 98–104
4. Tsai CJ, Ma BY, Nussinov R (1999) Folding and binding cascades: shifts in energy landscapes. Proc Natl Acad Sci U S A 96(18):9970–9972. doi:10.1073/pnas.96.18.9970
5. Tsai CJ, Kumar S, Ma BY, Nussinov R (1999) Folding funnels, binding funnels, and protein
function. Protein Sci 8(6):1181–1190
6. Boehr DD, Nussinov R, Wright PE (2009) The role of dynamic conformational ensembles in
biomolecular recognition. Nat Chem Biol 5(11):789–796. doi:10.1038/nchembio.232
7. Durrant JD, McCammon JA (2010) Computer-aided drug-discovery techniques that account
for receptor flexibility. Curr Opin Pharmacol 10(6):770–774. doi:10.1016/j.coph.2010.09.001
8. Totrov M, Abagyan R (2008) Flexible ligand docking to multiple receptor conformations: a
practical alternative. Curr Opin Struct Biol 18(2):178–184. doi:10.1016/j.sbi.2008.01.004
9. Carlson HA, McCammon JA (2000) Accommodating protein flexibility in computational
drug design. Mol Pharmacol 57(2):213–218
10. Carlson HA (2002) Protein flexibility is an important component of structure-based drug
discovery. Curr Pharm Des 8(17):1571–1578. doi:10.2174/1381612023394232
11. Chaudhury S, Gray JJ (2008) Conformer selection and induced fit in flexible backbone protein-protein docking using computational and NMR ensembles. J Mol Biol 381(4):1068–
1087. doi:10.1016/j.jmb.2008.05.042
12. Henzler-Wildman KA, Lei M, Thai V, Kerns SJ, Karplus M, Kern D (2007) A hierarchy of
timescales in protein dynamics is linked to enzyme catalysis. Nature 450(7171):913–U27.
doi:10.1038/nature06407