Can semiempirical methods be used for high throughput screening (for enzyme mutants)?

Cansemiempirical methodsbeusedforhighthroughputscreening?*(forenzymemutants)

JanH.Jensen,UniversityofCopenhagen

Feelfreetotweet,record,…#CompChemGRC

*Dunno yet,tryingtofindoutHere’sastatusreport

@janhjensen

1

AnearlyattemptTurningalipaseintoaamidase

Verdict:so-so

OnlyPM6predictscorrectmechanism

Hediger PLOSONE 2013Hediger PeerJ 2013

MOZYMEinMOPAC

2

1mutantpercoreper~24-32hrs

AnearlyattemptTurningalipaseintoaamidase

Verdict:nomutantswithhighamidaseactivity

👍 👎

Hediger PLOSONE 2013Hediger PeerJ 2013a

👍

👎

Highthroughputscreeningidentifiespotentially interestingmutantsforfurtherstudy

3

OptimizingaxylanaseforsyntheticsubstrateVedict:?? Hediger PeerJ 2013b

Allpossiblesinglemutants

Selectdoublemutants

4

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

5

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✔

6

Cansemiempirical methodsbeusedforhighthroughputscreening?pKa predictionVerdict:OK(ish) JensenArxiv 2015

Kromann PeerJ 2016

Amines

7

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

8

Cansemiempirical methodsbeusedforhighthroughputscreening?Openquestions/challenges

Howtoroutinely handle1000sofmolecules?(Ineedtolearncheminformatics)

Efficientconformersearchforproteins?

Automatic&robustTSsearch?

Improveaccuracybymachinelearning?

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

Multipurposeorproblem-specificmethods?

Experimentalvalidation/competition(Mustbebetter(&faster)thanexperimentalhighthroughput)

9

Guallar

Zimmerman,+…

vonLilienfeld

Reiher