Post on 21-Jan-2018
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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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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