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)