Chun Wu Research Assistant Professor University of California Santa Barbara

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1 Accurate bio-molecule model(force field) + China super computer: upgrade China s bio-research, pharmaceutical & bio-tech industries using molecular dynamics simulation Chun Wu Research Assistant Professor University of California Santa Barbara

2 Simulations in designing functional machines Dreamliner Reduce experiments Cut time Cut money

3 Simulations in designing functional electronic devices iphone Reduce experiments Cut time Cut money

Simulations in probing & optimizing bio-functional small molecules Thioflavin T(ThT) 350 compounds(11 grants & 10 yrs) PIB HIGH COST WAY 11 grants: NIH (AG018402, AG005133, AG001039, AG020226,

(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.

4 Simulations in probing & optimizing bio-functional small molecules Thioflavin T(ThT) 350 compounds(11 grants & 10 yrs) PIB HIGH COST WAY 11 grants: NIH (AG018402, AG005133, AG001039, AG020226, MH070729, MH001976, AG025516, AG025204), Alzheimer s Association (TLL ), 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 LOW COST WAY Binding sites Screening by simulations Binding abundance (10 days, 350 x 128=44,800 CPUs) Solvation Free energy Membrane crossing Reduce no. of trial compounds others Cut time Cut money Wu et al, Biophys J 100, p1316

of trial Cut time Cut money 70% KCNTATCATQRLANFLVH YTNSGVNTSSLIAGF S N S N Sub.

5 Simulations in optimizing functional biomolecules Human IAPP of Type II diabetes Optimized IAPP 4 mutations 4x128 CPUs for 20 days! 27% 12% 29% Reduce no. of trial Cut time Cut money 70% KCNTATCATQRLANFLVH YTNSGVNTSSLIAGF S N S N Sub. D-amino acids at loop region Dupuis-Wu-Shea-Bowers JACS 2010, & JACS Comm In press & in preparation

6 Why Molecular Dynamics (MD) matters? Life cycle Time Macro Man Dynamic picture from China philosophy Cell Yes Good to live? No Wrong picture from Static X-ray structure Micro Protein (movie) Biophysics Folding Binding Assembling Biochemsitry Synthesis Digesting

7 MD Simulations Time Nature :p585 Science :p585 Science 2010;330:341 McCammon Duan Shaw 3.2 x 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)

A real example: Discovery of Raltegravir (New class of AIDS

MD + Auto dock X-ray complex structure ( 5CITEP + IN) : 1QS4

et al PNAS 1999 96, p13040 Butterfly compound to enhance

8 A real example: Discovery of Raltegravir (New class of AIDS drugs) PARTIAL INFO SIMULATION & DOCK SAVE THIS DRUG AMBER 5 MD + Auto dock X-ray complex structure ( 5CITEP + IN) : 1QS4 Goldgur Y. et al PNAS , p13040 Butterfly compound to enhance binding affinity Schames-McCammon J Med Chem, 2004, 47, p1879 Hazuda DJ et Merck research Laboratories PNAS 2004, 101, p11233

Feb, 2006- Phase III Clinical Trial s Feb, 2007- Name announced Isentress

9 Simulation saves this drug MD Simulations & Docking Schames- McCammon J Med Chem, 2004, 47, p1879 AMBER 5 MD + Auto dock Imagination: butterfly compound Feb, Phase III Clinical Trial s Feb, Name announced Isentress (Raltegravir) Raltegravir Oct FAD Fast track approval Widely used drug for AIDS

research at molecular level Pharmaceudical industry

10 MD simulations: Great opportunity for China Accurate force field China Supercomputer Revolution Bio research at molecular level Pharmaceudical industry Biotech industry Chinese Medicine Hepatitis B Alzheimer s Cancer

ISI citations of AMBER ff03 NFGAIL of Amylin of Type II

of citations 150 100 50 0 Total 660+ 12 2002 2004 2006 2008

(2004) BJ, 88, p2897 Wu-Lei-Duan (2005) JACS, 127, p13530

s Wu-Bowers-Shea (2010) PLoS Comp Biol 6e1000693 AMBER ff03

11 ISI citations of AMBER ff03 NFGAIL of Amylin of Type II diabetes Citation trend of Amber ff No. of citations Total Year Wu-Lei-Duan (2004) BJ, 87, p3000 Wu-Lei-Duan (2004) BJ, 88, p2897 Wu-Lei-Duan (2005) JACS, 127, p13530 Wu-Lei-Wang-Zhang-Duan (2006) BJ, 91, 3664 Aβ40 of Alzheimer s Wu-Bowers-Shea (2010) PLoS Comp Biol 6e AMBER ff03 Duan, Wu, Chowdhury, Lee, Xiong, Zhang, Yang, Cieplak, Luo, Lee, Caldwell, Wang, Kollman

12 Replica exchange method Smaller trial interval, Better Exchange, Better sampling! But Increase communication overhead! NAMD (script) Sugita Y. et al. Chem Phys Lett 314 (1999) p141 Hukushima, K et al (1996) J Phys Soc Jpn 65, p1604

13 Parallel replica exchange using MPI (message passing interface) mpi_group_incl mpi_scatter mpi_bcast T i E i master mpi_gather Sander 7 Temp 1 Grandmaster Monte Carlo master Temp 2 master Temp3 zhang-wu-duan, (2005) JCP, 123, !

replica exchange) AMBER ff03+igb5 AK16 16

14 Correct folding helical proteins from extended conformation ~10 X (Parallel replica exchange) AMBER ff03+igb5 AK16 16 amino acid FS a. a. Lei-Wu-Liu-Duan (2007) PNAS, 104, 4925 Lei-Wu-Wang-Zhou-Duan (2008) JCP, 128, Lei-Wang-Wu -duan (2009) JCP 131, HP35 35 a. a. Protein A 60 a. a. High resolution structural prediction!

15 SIMULATE YOUR MOLECULS!? Drug delivery Acetyl CoA carboxylase

16 Acknowledgement Duan Group Shea Group Bowers Group Wang Group (Force field improvement) Lei Group (DNA-drug binding) AMBER 11 Powered by GPU Dr. Wei Zhang (drug discovery)