Computational Modelling of Chemical and Biochemical Reactivity Chemistry Ian Williams
Jan 24, 2016
Computational Modelling of Chemical and Biochemical
Reactivity
Chemistry
Ian Williams
BathBath English Lake District
Buttermere
Borrowdale
Honister Pass
Youth Hostel + car park
BC D
TE
W GR
W
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A Chemical Landscape:mountain pass ‡ transition state
Epeak
Epass
geometry
the transition state ‡ of amolecular system controls the direction and rate of chemical change betweenreactants R and products P
Map coordinates: longitude & latitude
Contour lines: vertical height potential energy (gravitational)
glyco
pro
tein
O
cell
sialic acid
Relenza and Tamiflu stop the virus
from budding out of the cell
neuraminidase
37 atoms
85 atoms
quantummechanics:Schrödinger
equation
37 atoms
85 atoms
quantummechanics:Schrödinger
equation
Neuraminidase5668 atoms
classical mechanics: Hooke & Coulomb
37 atoms
85 atoms
quantummechanics:Schrödinger
equation
5668 atoms
Neuraminidase 5668 atoms
Neuraminidase in water: 50177 atoms
MMQMQM/MM
“QM/MM”
Etotal = EQM + EMM + EQM/MM
quantum classical
interaction
QM only
too many electrons
MM only
cannot treatcannot treatelectronic electronic
reorganisationreorganisation
Quantum mechanics Molecular mechanics
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TYR
ASP
GLU
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~36 CPU hrs per point
on 2D projection of
~105D QM/MM PE surface
Elaboration of series of MD simulations along an appropriate coordinate using a biasing potential
Molecular dynamics: Newton’s Laws
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
Potential of Mean Force Free energy changescorresponding to chemical kinetics and equilibria
timescale
Pople: systematic improvement of QM
methodselectron correlation
basis set
• systematic improvement of QM/MM MD simulations requires simultaneous advances in multiple dimensions, each one being computationally demanding
MM atomsdegrees of freedom
exchange/correlation
functional
Chemistry machine room:• ~ 30 x Pentium PCs running Linux
• 3 x dual 2.2 GHz AMD Opteron, 2 x 4 Gb + 1 x 8 Gb memory, 2 x 80 Gb + 1 x 300 Gb disk
IHW group’s computing resources at Bath
BUCS machine room:• Share of Skein (HEFCE JREI, May 2002)
• Upgrade 2007 with EPSRC funding (awarded)• Further BBSRC pending decision
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
Thank you for listening!