Industrial Strength QM/MM: Computa8onal high throughput screening of enzyme ac8vity in enzyme mutants Jan H. Jensen , Mar$n Hediger, Luca De Vico, Kasper Primdal, Allan Svendsen, Werner Besenma=er Department of Chemistry University of Copenhagen MarFn R. Hediger, Luca De Vico, Allan Svendsen, Werner Besenma=er, Jan H. Jensen “A ComputaFonal Methodology to Screen AcFviFes of Enzyme Variants” PLoS ONE, submi=ed. h=p://arxiv.org/abs/1203.2950 Slides at: h=p://Fnyurl.com/bsqbojf
Recording of the talk: http://proteinsandwavefunctions.blogspot.com/2012/05/my-talk-at-irene-meeting.html
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Industrial Strength QM/MM: Computa8onal high throughput screening of enzyme ac8vity in enzyme mutants
Jan H. Jensen, Mar$n Hediger, Luca De Vico, Kasper Primdal, Allan Svendsen, Werner Besenma=er
Department of Chemistry University of Copenhagen
MarFn R. Hediger, Luca De Vico, Allan Svendsen, Werner Besenma=er, Jan H. Jensen “A ComputaFonal Methodology to Screen AcFviFes of Enzyme Variants” PLoS ONE, submi=ed.
h=p://arxiv.org/abs/1203.2950
Slides at: h=p://Fnyurl.com/bsqbojf
Goal
Automated predicFon of barrier height for enzymaFc reacFon within 24 hr using < 10 cores IdenFfies promising candidates for further study
Industrial enzyme design
High-‐through put screening of 100s of mutants IdenFfies promising candidates for further study
ComputaFonal predicFon: Homology modeling
QSAR (QM or QM/MM too slow and lacks automaFon) IdenFfies promising candidates for further study
Further study: 20-‐50 mutants
Slides at: h=p://Fnyurl.com/bsqbojf
Methods
PM6 implemented in Mopac2009 (MOZYME)
Automated mutant builder (PYMOL)
Barrier from adiabaFc mapping
Applica$on Increase amidase acFvity in an estarase (CalB)
MarFn R. Hediger, Luca De Vico, Allan Svendsen, Werner Besenma=er, Jan H. Jensen “A ComputaFonal Methodology to Screen AcFviFes of Enzyme Variants” PLoS ONE, submi=ed.
PM6 is good enough
PM6 and MOZYME MOZYME = PM6 computed with MOZYME
PM6 = PM6//MOZYME MOZYMEReortho = MOZYME//MOZYME
PM6/MOZYME is fast enough
MOPAC2009 No parallelized
55 aa
PM6/MOZYME is fast enough
OpFmizaFon Single point
Future Direc$ons
Whole protein COSMO solvaFon
More automaFzaFon Be=er sampling
Complete scan of single mutants Single -‐> double -‐> triple mutants
PM6 in GAMESS Linear scaling PM6 PM6/PCM interface
AlternaFves to adiabaFc mapping
Beyond PM6: EFMO
Blurring the boundary between linear scaling QM, QM/MM and polarizable force fields
The Effec@ve Fragment Molecular Orbital Method
Jan H. Jensen, Casper Steinmann, Mikael Wistoi Ibsen, Kasper Thoie University of Copenhagen
Dmitri Fedorov AIST, Japan
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Casper Steinmann, Dmitri G. Fedorov, and Jan H. Jensen “The EffecFve Fragment Molecular Orbital Method: A Merger of the Fragment Molecular Orbital and EffecFve Fragment PotenFal Methods” Journal of Physical Chemistry A 2010, 114, 8705-‐8712
Casper Steinmann, Dmitri G. Fedorov, and Jan H. Jensen “The EffecFve Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds” PLoS ONE, submi=ed. h=p://arxiv.org/abs/1202.4935
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The Effec$ve Fragment Molecular Orbital (EFMO) method Using ideas from the EffecFve Fragment PotenFal (EFP) and the Fragment Molecular Orbital (FMO) method
The Effec$ve Fragment Molecular Orbital (EFMO) method (Using ideas from the EffecFve Fragment PotenFal (EFP) method)
Monomer SCF in the gas phase
Extract mulFpoles and dipole polarizability
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The Effec$ve Fragment Molecular Orbital (EFMO) method (Using ideas from the EffecFve Fragment PotenFal (EFP) method)
Many-‐body polariza$on
Computed classically using induced dipoles for enFre system
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The Effec$ve Fragment Molecular Orbital (EFMO) method (Using ideas from the EffecFve Fragment PotenFal (EFP) method)
Coulomb and Non-‐Coulomb effects
dimer SCF in the gas phase
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The Effec$ve Fragment Molecular Orbital (EFMO) method (Using ideas from the EffecFve Fragment PotenFal (EFP) method)