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

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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!