Adventures in Computational Chemistry McCammon Group, UCSD/HHMI

Prehistory, – Sputnik; International Geophysical Year 1958 – Disney’s “Man-in-Space” Comic Book 1959 – Discovery of the Parabola 1960 – Mysterious holes in Cordova Street – Nerdy years in high school, encouraged by chemistry teachers!

Pomona College, Corwin Hansch winner in 1999 IBM 360 Summers at MIT, Berkeley, Harvard Anne

Harvard, etc., – Chemical Physics – Drafted! MGH years – Collapse of Experimentalist Dreams – Rescued by a Theoretical Chemist from MIT… – 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

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 MK-0518 February, 2006 – Phase III Clinical Trials February, 2007 – Name announced: Isentress (raltegravir) October, 2007 – FDA “fast track” approval

Accelerated MD for the molecular components Hamelberg, Mongan & McCammon, J. Chem. Phys. (2004)

Accelerated MD Hamelberg, Mongan & McCammon, J. Chem. Phys. (2004)

Protein GB3: Dynamics by NMR Markwick, Bouvignies & Blackledge, J. Amer. Chem. Soc. (2007)

Accelerated MD and NMR: Protein GB3 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