Post on 15-Apr-2017
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Cansemiempirical methodsbeusedforhighthroughputscreening?*(forenzymemutants)
JanH.Jensen,UniversityofCopenhagen
Feelfreetotweet,record,…#CompChemGRC
*Dunno yet,tryingtofindoutHere’sastatusreport
@janhjensen
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AnearlyattemptTurningalipaseintoaamidase
Verdict:so-so
OnlyPM6predictscorrectmechanism
Hediger PLOSONE 2013Hediger PeerJ 2013
MOZYMEinMOPAC
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1mutantpercoreper~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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NeedPM6in“opensource”programtoproceedImplementingPM6inGAMESS
PM6&DFTBnowinAmberTools
PM6uptoFluorine✔PM6/PCMuptoF✔PM6-D3H+✔PM6for>FLinearscalingPM6QM/MMPM6
Kromann unpublishedSvendsen PLOSONE 2013Kromann PeerJ 2014
LinearscalingDFTB✔DFTB/PCM✔QM/MMDFTB
NishimotoCPL 2015NishimotoJPCA 2016
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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?pKa predictionVerdict:OK(ish) JensenArxiv 2015
Kromann PeerJ 2016
Amines
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Cansemiempirical methodsbeusedforhighthroughputscreening?pKa prediction JensenarXiv 2015
Kromann PeerJ Preprints2016
ChemAxonEt3NRefaRefbExperiment
9.1-0.20.10.74.2
Refa
Refb
CPUtime~3min/core/conformer
PM6/COSMO
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Cansemiempirical methodsbeusedforhighthroughputscreening?Openquestions/challenges
Howtoroutinely handle1000sofmolecules?(Ineedtolearncheminformatics)
Efficientconformersearchforproteins?
Automatic&robustTSsearch?
Improveaccuracybymachinelearning?
machinelearning+(DLNPO)CCSD(T)=newsemiempirical methods?
Multipurposeorproblem-specificmethods?
Experimentalvalidation/competition(Mustbebetter(&faster)thanexperimentalhighthroughput)
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Guallar
Zimmerman,+…
vonLilienfeld
Reiher