QuantumBiochemistryor

ComputationalEnzymeDesign– astatusreport

JanH.Jensen,UniversityofCopenhagen

@janhjensen

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ComputationalEnzymeDesignTwomainapproaches

QM/MM TSDocking

👍 Accurate

👎 Slow,3-5mutants👍 Fast,100- 10,000mutants

👎 Approximate

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ComputationalEnzymeDesignAthirdway:Semiempirical QM

SQM/MM

👍 Accurateenough(?)Fast,100-1000mutants(?)

ForceField

QuantumMechanicsSQM

FastApproximate

SlowAccurate

👍

AnearlyattemptTurningalipaseintoaamidase

Verdict:so-so

OnlyPM6predictscorrectmechanism

Hediger PLOSONE 2013Hediger PeerJ 2013

MOZYMEinMOPAC

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1mutantperCPUper~24-32hrs

AnearlyattemptTurningalipaseintoaamidase

Verdict:nomutantswithhighamidaseactivity

👍 👎

Hediger PLOSONE 2013Hediger PeerJ 2013a

👍

👎

Highthroughputscreeningidentifiespotentially interestingmutantsforfurtherstudy

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OptimizingaxylanaseforsyntheticsubstrateVedict:?? Hediger PeerJ 2013b

Allpossiblesinglemutants

Selectdoublemutants

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HowaccuratearePM6andDFTBforenzymebarrierheights?Verdict:4(ish)outof5forbothmethods

Kromann,CuiPeerJ 2016

Himo:B3LYP/6-311+G(2d,2p)[LANL2DZ]//B3LYP/6-31G(d,p)

PM6✔DFTB✔PM6✔

DFTB✘PM6✘DFTB✔

PM6✔DFTB✔

PM6✔DFTB✔

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pKa prediction:ameasureofchemicalreactivityVerdict:OK!

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Kromann PeerJ 2016JensenJ.Phys.Chem.A2017

Cansemiempirical methodsbeusedforhighthroughputscreening?Openquestions/challenges

Efficientconformersearchforproteins?

Automatic&robustTSsearch?

Improveaccuracybymachinelearning?

machinelearning+(DLNPO)CCSD(T)=newsemiempirical methods?

Multipurposeorproblem-specificmethods?

Experimentalvalidation/competition(Mustbebetter(&faster)thanexperimentalhighthroughput)

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