Potential of Mean Force of Ion Permeation through alpha7 nAChR Ion Channel
September 29th 2009
Dr. Jens Krüger
AK Fels
University of Paderborn
Outline
• Neuroreceptors
• Ion Permeation
• Simulation Performance
• Wishlist
http://oreilly.com/medical/bipolar/graphics/bpd0102.gif
Synaptic Cleft
50 nm
nAChR
based on Unwin, N. (2005) J. Mol. Biol. 346(4): 967‐989. Transistor
Source
Gate
Drain
Receptor (nAChR)
Extracellular
Neurotransmitter
Binding of two agonist molecules (e.g. acetylcholine) to the extracellular part triggers the opening of the channel, wich is over 20 Å away.
Intracellular
Single Channel nAChR
Shao, Z., Yakel, J. (2000) Journal of Physiology 527:3 507‐513. Water density
unbound bound
Plasticity
Changeux, J.‐P., Danchin, A. (1976) Nature 264: 705‐712.
Ion Permeation
SMD Pulling
• virtual spring
– moves from point A to B
– takes a certain time
– has a certain spring constant
• object pulled
– has a defined starting point
– follows the spring
– can be faster than the spring
• reference group
– all movements of the spring are relative to it
– good to compensate for small movements in the total simulation system
Umbrella Sampling
• virtual spring
– located along the reaction coordinate
– does not move
– has a certain spring constant
• object constrained
– has a defined starting point
– follows the spring
– can move above or below the spring
• reference group
– all movements of the spring are relative to it
– good to compensate for small movements in the total simulation system
Potential of Mean Force
SMD pulling
Umbrella Sampling
Nz
PMF ( z ) = ∑ ( ΔFn − γ Δzn / Δtn )Δzn
PMF ( z ) = − k BT ln( P ( z ) / P0 )
n =1
Treatment of friction is highly important
• 1 simulation (2100ps) yields 1 PMF
• 12 repititions for reasonable error estimate
•
Sensitive to starting configuration and ion placement
• 300 simulations (300ps) yields 1 PMF
• 3 reptitions for reasonable error estimate
•
PMF ( zstart ) = PMF ( zend ) = 0
Hydration Shell
SMD PMF
influx
eflux
Pulling Speed
US PMF
Clusters and Middleware
• Bisgrid 2 quadcore Intel X5355 (2.66 GHz) per node, Infiniband, Unicore 5.6 (http://www.unicore.eu/)
• Arminius 2 singlecore Intel XeonDP (3.2 GHz) per node, Infiniband, CCS (https://www.openccs.eu/core/)
Performance
Bisgrid 2 quadcore Intel X5355 (2.66 GHz) per node, Infiniband
Arminius 2 singlecore Intel XeonDP (3.2 GHz) per node, Infiniband
Speedup
Bisgrid 2 quadcore Intel X5355 (2.66 GHz) per node, Infiniband
Arminius 2 singlecore Intel XeonDP (3.2 GHz) per node, Infiniband
Relative Performance
Bisgrid 2 quadcore Intel X5355 (2.66 GHz) per node, Infiniband
Arminius 2 singlecore Intel XeonDP (3.2 GHz) per node, Infiniband
Comparison based on Arminius
Steered MD
• 2x 12 repititons
• 2100 ps length each
• 18 h on 32 cores
• 750 MB output
Umbrella Sampling
• 300 repititions
• 300 ps length each
• 7.8 h on 4 nodes
• 150 MB output
• 6490 CPU hours are required for 2x 12 runs
• 9360 CPU hours are required for 3x 300 runs
Wishlist for a Portal
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Combined workflow (command‐line and GUI)
Transparent queuing system
Multiple input sources
Intelligent parameter sweep
Handling of large amounts of data (> 1 GB)
Flexible data storage
Continious progress report
Real time application output
Acknowledgment
Paderborn
• Gregor Fels
• Brigitta Elsässer
• Markus Tusch
• Lars Haller
• Iris Baum
• Oliver Stücker
• The Paderborn Center for Parallel Computing (PC2)
• Alexander‐von‐Humboldt Foundation
• Taiwanese Government, National Science Council and NYMU