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Adventures in Computational Chemistry
McCammon Group, UCSD/HHMI
Prehistory, 1957-1965
1957 – Sputnik; International Geophysical Year
1958 – Disney’s “Man-in-Space” Comic Book
1959 – Discovery of the Parabola
1960 – Mysterious holes in Cordova Street
1961-65 – Nerdy years in high school, encouraged by chemistry teachers!
Pomona College, 1965-1969
Corwin Hansch
winner in 1999
IBM 360
Summers at MIT, Berkeley, Harvard
Anne
Harvard, etc., 1969-1978
1969-70 – Chemical Physics
1970-72 – Drafted! MGH years
1972-74 – Collapse of Experimentalist Dreams
1974-76 – Rescued by a Theoretical Chemist from MIT…
1976-78 – Computational Chemistry, at Last !
Lysozyme, the Hinge-bending Mode
McCammon, Gelin, Karplus & Wolynes, Nature (1976)
Molecular Dynamics Simulation
McCammon, Gelin & Karplus, Nature (1977)
Brownian Dynamics Simulation• Solvent effects included in:
– Implicit solvent electrostatics forces
– Hydrodynamics– Random solvent forces
• Useful for:– Bimolecular rate
constants– Conformational
sampling– Dynamical properties Animation courtesy of Dave Sept
Ermak & McCammon , J. Chem. Phys. (1978)Northrup, Allison & McCammon, J. Chem. Phys. (1984)
Computational Alchemy
Wong & McCammon, J. Amer. Chem. Soc. (1986)
HIV/AIDS
1981: AIDS first described
1983: retrovirus HIV-1 identified
HIV-1 Enzymes:
Reverse Transcriptase (RNA to DNA)
Integrase (DNA into human genome)
Protease (Makes pieces of new HIV)
Target Flexibility
HIV-1 Protease
AIDS Deaths in the US
0
10000
20000
30000
40000
50000
60000
Relaxed Complex Method
Protein “snapshots” from simulation Rapid docking of ligand to snapshots Rescoring for higher accuracy Two-site binders with flexible linkers
Lin, Perryman, Schames & McCammon, J. Amer. Chem. Soc. (2002)
Initial Tests with FKBP-12
Standard MD in water, 2 ns
Fluctuation of Binding Site
Goldgur, …& Davies, Proc. Natl. Acad. Sci. USA (1999)
HIV Integrase and 5CITEP
Goldgur, …& Davies, Proc. Natl. Acad. Sci. USA (1999)
5CITEP Contacts Between Neighbors
Initial Relaxed Complex Results
Carlson & McCammon, Molec. Pharmacol. (2000)Schames, … & McCammon, J. Med. Chem. (2004)
Butterfly Compounds
Schames, … & McCammon, J. Med. Chem. (2004)
The New Merck Strategy
Schames, … & McCammon, J. Med. Chem. (2004)
New Class of HIV Drugs: Merck & Co.
“the structural basis for this unexpected result …suggests an approach to the development of integrase inhibitors with unique resistance profiles.”
D. Hazuda et al., Proc. Natl. Acad. Sci. USA (2004), refers to Schames, et al. (2004).
Discovery of unexpected binding site in HIV-1 Integrase using MD and AutoDock: Schames, … & McCammon, J. Med. Chem. (released on web, March 2004)
L-870812 MK-0518
February, 2006 – Phase III Clinical TrialsFebruary, 2007 – Name announced: Isentress (raltegravir)October, 2007 – FDA “fast track” approval
Accelerated MD for the molecular components
V(x
)V
(x)
x
α =1α= 50α= 100
Hamelberg, Mongan & McCammon, J. Chem. Phys. (2004)
Accelerated MD
EVVV
EVVV
(r)(r),(r)
(r)(r),(r)
(r))(
(r)(r)
2
VE
VEV
Hamelberg, Mongan & McCammon, J. Chem. Phys. (2004)
Protein GB3: Dynamics by NMR
Markwick, Bouvignies & Blackledge, J. Amer. Chem. Soc. (2007)
S
2NHRDC,S 2
NHLS,S
Accelerated MD and NMR: Protein GB3
2NHRDC,S
2NHLS,S
MD
NMR
MD
NMR
Markwick, Bouvignies & Blackledge, J. Amer. Chem. Soc. (2007)
Structural Design
Acknowledgments grad. students postdocs senior collabs. Arneh Babakhani Rommie Amaro Seth Cohen Nathan Baker Riccardo Baron Mike Holst Jennifer Bui Heather Carlson Robert Konecny Yuhui Cheng Chia-en Chang Jeremy Kua David Minh Xiaolin Cheng Jung-Hsin Lin John Mongan Alemayehu Gorfe Art Olson Alex Perryman Barry Grant Steve Sine Julie Schames Donald Hamelberg Palmer Taylor Tongye Shen Richard Henchman Susan Taylor Jason Smart Ben-Zhuo Lu Valentina Tozzini Jessica Swanson Cameron Mura Joanna Trylska Kaihsu Tai Dave Sept Chung Wong Sylvia Tara Sarah Williams Yingkai Zhang David Zhang