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