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Semelhante a The 2013 Bjerrum-Brønsted-Lang Lecture: quantum biochemistry and the rise of semiempirical methods and automation in quantum chemistry (20)
The 2013 Bjerrum-Brønsted-Lang Lecture: quantum biochemistry and the rise of semiempirical methods and automation in quantum chemistry
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Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 2
Quantum Biochemistry
Jan H. Jensen
Department of Chemistry
University of Copenhagen
Slides can be found at: tinyurl.com/bbl2013
June 18, 2013
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Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 3
Computational Chemistry
The underlying physical laws necessary for the mathematical
theory of a large part of physics and the whole of chemistry are
thus completely known, and the difficulty is only that the exact
application of these laws leads to equations much too
complicated to be soluble.
Paul Dirac, 1929
i
∂
∂t
Ψ = ˆHΨ
Schrödinger Equation (1926)
Not anymore!
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CCSD(T)/CBS: benchmarking faster methods
CCSD(T)/CBS currently too “slow” for routine chemical
applications, but …
CCSD(T)/CBS now sufficiently “fast” to generate large amounts
of data for benchmarking faster methods
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 5
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The rise of semi-empirical methods
Semi-empirical methods: quantum mechanical (QM) methods
with fitted parameters
Fitting and validation can now done using CCSD(T)/CBS instead
of experimental data: a huge conceptual and practical
advance.
Better QM: fewer parameters and wider applicability
Examples: DFT-D, PM6-DH+, HF-3c
HF-3c: HF/minimal basis set corrected for dispersion & BSSE
using 9 parameters. No experimental input.
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 6
Grimme: 10.1002/jcc.23317
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Validation against experiment: ΔG
Fast methods frequencies free energies
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 8
MAD: 2.1 kcal/mol
Grimme: 10.1002/chem.201200497
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Semi-empirical methods: new horizons
QM structures and free energies for large systems
Accurate protein structures
Accurate activation free energies for enzymatic reactions
Accurate binding free energies for protein-ligand complexes
Automation and Computational High-Throughput Screening
NMR chemical shift prediction for proteins
Screening enzyme mutants
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 9
Grimme: 10.1002/chem.201200497
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QM structures and free energies for proteins
Large systems require different algorithms
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 10
The Effective Fragment Molecular Orbital Method
Jan H. Jensen, Anders Christensen and
Casper Steinmann (SDU)
University of Copenhagen
Dmitri Fedorov
AIST, Japan
JPC A 2010, 114, 8705
PLoS ONE 2012, 7:e41117
PLoS ONE 2012, 7:e44480
PLoS ONE 2013, 8: e60602
arxiv:1305.0676
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Systematic Screening of Enzymatic Reaction Barriers
Martin Hediger and Luca De Vico
Allan Svendsen (Novozymes)
PLoS ONE 2012 7:e49849
PeerJ, submitted (arXiv:1305.6049)
arXiv:1209.4469
Automation and High-Throughput Screening
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 13
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Automation and High-Throughput Screening
All possible single mutations PM6 barrier
combination mutants
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 14
ca 500-1000 mutants can be screened
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Automation and High-Throughput Screening
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 15
Proteins Structure Determination from Chemical Shifts
Anders Christensen (Novo Nordisk STAR PhD) & Lars Bratholm
Thomas Hamelryck, Kresten Lindorff-Larsen, Kaare Teilum (BIO)
JCTC 2011, 7 2078
JACS, submitted (arXiv:1305.2164)
10.1021/ar900068s
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A fast chemical shift predictor for proteins
Representative fragments QM calculations empirical
model
QM calculations benchmarked against CCSD(T)
Between 500,000 and 1,000,000 QM calculations needed
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 16
arXiv:1305.2164
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Summary
CCSD(T)/CBS: Experimental accuracy for small, but now chemically
relevant, molecules.
CCSD(T)/CBS replaces experiment for parameterization and
validation of faster semi-empirical QM methods: more thorough
and rigorous parameterization leads to more generally applicable
methods.
New semi-empirical QM methods are now finally sufficiently
accurate to be of practical use.
New semi-empirical methods are sufficiently fast for high-
throughput screening (1000-1,000,000 QM calculations): new
molecular design ideas for experimental chemists.
Quantum chemists need to adapt: automation/cheminformatic
considerations should be integral part of new modeling projects.
Department of Chemistry
2013 Bjerrum-Brønsted-Lang Lecture
Dias 17
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Department of Chemistry
Dias 19
2013 Bjerrum-Brønsted-Lang Lecture