Computational Modelling of Chemical and Biochemical Reactivity

1. Computational Modelling of Chemical and Biochemical Reactivity Ian Williams Chemistry

2. Buttermere Borrowdale Honister Pass English Lake District Bath Youth Hostel + car park

3. A Chemical Landscape:mountain pass ‡º transition state the transition state‡of amolecular system controls the direction and rate of chemical change betweenreactants R and products P DEpeak DEpass geometry D ‡ C B E T ‡ ‡ ‡ ‡ ‡ ‡ Map coordinates: longitude & latitude Contour lines: vertical height µ potential energy (gravitational) W G R ‡ W

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5. Relenza and Tamiflu stop the virus from budding out of the cell

6. 37 atoms 85 atoms quantummechanics:Schrödinger equation neuraminidase

7. 37 atoms 85 atoms Neuraminidase5668 atoms quantummechanics:Schrödinger equation

8. Neuraminidase5668 atoms 5668 atoms 37 atoms quantummechanics:Schrödinger equation Neuraminidase in water: 50177 atoms classical mechanics: Hooke & Coulomb 85 atoms

9. QM only MM only cannot treatelectronic reorganisation too many electrons “QM/MM” Etotal = EQM + EMM + EQM/MM quantumclassical interaction QM MM QM/MM Quantum mechanics Molecular mechanics

10. TYR GLU ASP ~36 CPU hrs per point on 2D projection of ~105D QM/MM PE surface ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡

11. Molecular dynamics: Newton’s Laws Elaboration of series of MD simulations along an appropriate coordinate using a biasing potential ÞPotential of Mean ForceÞFree energy changescorresponding to chemical kinetics and equilibria T = 300KQM/MM potential for 50,000 atoms within periodic boundary conditions A typical MD trajectory within an “umbrella sampling” window takes ~10 CPU days to perform 20 ps equilibration + 20 ps production run to average over the sampled configurations

12. Pople: systematic improvement of QM methods electron correlation basis set timescale MM atoms degrees of freedom exchange/correlationfunctional • systematic improvement of QM/MM MD simulations requires simultaneous advances in multiple dimensions, each one being computationally demanding

13. IHW group’s computing resources at Bath Chemistry machine room: • ~ 30 x Pentium PCs running Linux • 3 x dual 2.2 GHz AMD Opteron, 2 x4 Gb + 1 x 8 Gb memory, 2 x 80 Gb + 1 x 300 Gb disk BUCS machine room: • Share of Skein (HEFCE JREI, May 2002) Pauling(BBSRC, June 2005) Linux (SUSE 9) cluster with: • 1 x Front-end dual 2.2 GHz AMD Opteron, 2 Gb memory, 1 Tb RAID 5 • 32 x (dual 2.4 GHz CPU, 4 Gb memory, 120 Gb disk) • 4 x (dual-core dual 2.2 GHz CPU, 8 Gb memory, 120 Gb disk) • Gigabit interconnect • Upgrade 2007 with EPSRC funding (awarded) • Further BBSRC pending decision Thank you for listening!