accurate bio-molecule model(force field) - ucsbcwu/gallery/paperpdb/china_v0_b.pdf · isi citations...
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Accurate bio-molecule model(forcefield) + China super computer: upgrade China’s bio-research,
pharmaceutical & bio-tech industries using molecular dynamics simulation
Chun WuResearch Assistant Professor
University of California Santa Barbara2011
http://www.chem.ucsb.edu/~cwu
Simulations in designing functional machines
•Reduce experiments•Cut time •Cut money
Dreamliner
Simulations in designing functional electronic devices
•Reduce experiments•Cut time •Cut money
iPhone
Simulations in probing & optimizing bio-functional small molecules
PIBThioflavin T(ThT)
11 grants: NIH (AG018402, AG005133, AG001039, AG020226, MH070729, MH001976, AG025516, AG025204), Alzheimer’s Association (TLL-01-3381), GE Healthcare and the US Department of Energy (DE-FD02-03 ER63590)
“From that Time(1999) through our present work (2008) with fluorine-18–
labeled PiB derivatives, we have synthesized and tested over 350 thioflavin-T derivatives.”
William E. Klunk, MD, PhD* and Chester A. Mathis, PhD
•Screening by simulations(10 days, 350 x 128=44,800 CPUs)
•Reduce no. of trial compounds •Cut time•Cut money
Binding sitesBinding abundanceSolvation Free energyMembrane crossingothers
350 compounds(11 grants & 10 yrs)
Wu et al, Biophys J 100, p1316
HIGHCOSTWAY
LOWCOSTWAY
Simulations in optimizing functional biomolecules
Human IAPP of Type II diabetes
27% 12% 29%
Sub. D-amino acids atloop region
KCNTATCATQRLANFLVH
YTNSGVNTSSLIAGF
SNS
N
•Reduce no. of trial•Cut time•Cut money
70%
4 mutations4x128 CPUs for 20 days!
Optimized IAPP
Dupuis-Wu-Shea-Bowers JACS 2010, 131 18283 & JACS Comm In press & in preparation
Why Molecular Dynamics (MD) matters ?Life cycle Time
•Biophysics•Folding•Binding•Assembling
•Biochemsitry•Synthesis•Digesting
Micro
Macro
Man
Cell
Protein(movie)
www.youtube.com/watch?v=u04oBGzQZPw
Wrong picture fromStatic X-ray structure
Dynamic picture from China philosophy
Good to live?
Yes No
MD SimulationsTime
Science 2010;330:341Nature1977 267:p585 Science 1998 267:p585
3.2 x 10-12 s/ps • ~20,000 atoms• 1 x 10-6 s
• AMBER ff94•60 day 256-CPU
• ~26,000 atoms• 100 x 10-6 s
• AMBER ff99SB• 60 day(?) 512-special-CPU(ASIC)
# 6 of 10 scientific breakthroughs by Science magazine (2010)
McCammon Duan Shaw
A real example: Discovery of Raltegravir (New class of AIDS drugs)
X-ray complex structure( 5CITEP + IN) : 1QS4Goldgur Y. et al PNAS 1999 96, p13040
Butterfly compound to enhance binding affinity Schames-McCammonJ Med Chem , 2004, 47, p1879
Hazuda DJ et Merck research Laboratories PNAS 2004, 101, p11233
AMBER 5 MD + Auto dockAMBER 5 MD + Auto dockAMBER 5 MD + Auto dockAMBER 5 MD + Auto dock
SAVE THIS DRUGSIMULATION & DOCKPARTIAL INFO
Simulation saves this drug
Feb, 2006- Phase III Clinical Trial’sFeb, 2007- Name announced
Isentress (Raltegravir)
Oct. 2007-FAD “Fast track” approvalWidely used drug for AIDS
Raltegravir
MD Simulations & DockingSchames- McCammonJ Med Chem , 2004, 47, p1879
AMBER 5 MD + Auto dock Imagination: butterfly compound
MD simulations:Great opportunity for China
Accurate force field Revolution– Bio‐research at molecular level
– Pharmaceudicalindustry
– Biotech industry
Hepatitis B
Alzheimer’s
Cancer
ChinaSuper-computer
ChineseMedicine
ISI citations of AMBER ff03
Citation trend of Amber ff03
0
50
100
150
200
2002 2004 2006 2008 2010 2012
Year
No.
of c
itat
ions
180
12
Total 660+Wu-Lei-Duan (2004) BJ, 87, p3000Wu-Lei-Duan (2004) BJ, 88, p2897Wu-Lei-Duan (2005) JACS, 127, p13530Wu-Lei-Wang-Zhang-Duan (2006) BJ, 91, 3664
Wu-Bowers-Shea (2010) PLoS Comp Biol 6e1000693
NFGAIL of Amylin of Type II diabetes
Aβ40 of Alzheimer’s
AMBER ff03 Duan, Wu, Chowdhury, Lee, Xiong, Zhang, Yang, Cieplak, Luo, Lee, Caldwell, Wang, Kollman
Replica exchange method
Sugita Y. et al. Chem Phys Lett 314 (1999) p141Hukushima, K et al (1996) J Phys Soc Jpn 65, p1604
• Smaller trial interval, Better Exchange, Better sampling!• But Increase communication overhead!
NAMD (script)
Parallel replica exchange
using MPI (message passing interface)
Grandmaster
master Temp 1
master Temp 2
master
worker
worker
worker
worker
worker
worker
worker
worker
worker
Temp3
mpi_gather
mpi_scatter
mpi_bcast
Monte Carlo
mpi_group_inclTi Ei
zhang-Wu-Duan, (2005) JCP, 123, 154105 !
Sander 7
Correct folding helical proteins from extended conformation
Lei-Wu-Liu-Duan (2007) PNAS, 104, 4925Lei-Wu-Wang-Zhou-Duan (2008) JCP, 128, 235105Lei-Wang-Wu -duan (2009) JCP 131, 165105
•~10 X (Parallel replica exchange)• AMBER ff03+IGB5
AK1616 amino acid
FS-2121 a. a.
Protein A60 a. a.
HP3535 a. a.
High resolution structural prediction!
SIMULATE YOUR MOLECULS!?
Acetyl CoA carboxylaseDrug delivery
Acknowledgement
Wang Group(Force field improvement)
Powered by GPU
AMBER 11
Shea Group Bowers Group
Duan Group
Lei Group (DNA-drug binding)
Dr. Wei Zhang (drug discovery)