xxxvi int. congress of phys. sci. tutorial-3 #2 structural ...jul 29, 2009 · large red: x-ray...

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Tutorial-3 #2 Structural modeling of proteins: Principle and application to an ion channel Haruki Nakamura PDBj, Institute for Protein Research, Osaka University Daron M. Standley Immunology Frontier Research Center, Osaka University Narutoshi Kamiya The center for Advanced Medical Engineering and Informatics, Osaka University http://www.protein.osaka-u.ac.jp/rcsfp/pi/ http://www.pdbj.org/ XXXVI Int. Congress of Phys. Sci. TU-3 July 29, 2009

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Page 1: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Tutorial-3 #2Structural modeling of proteins:

Principle and application to an ion channel

Haruki NakamuraPDBj, Institute for Protein Research, Osaka University

Daron M. StandleyImmunology Frontier Research Center, Osaka University

Narutoshi KamiyaThe center for Advanced Medical Engineering and Informatics, Osaka University

http://www.protein.osaka-u.ac.jp/rcsfp/pi/http://www.pdbj.org/

XXXVI Int. Congress of Phys. Sci.TU-3 July 29, 2009

Page 2: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Protein Data Bank Japan

http://www.pdbj.org/

At Institute for Protein Research, Osaka Univ. since 2001 supported from the Institute for Bioinformatics Research and Development, Japan Science and Technology Agency (BIRD-JST).

Structure Data curationand editing

Structure Data browsing and downloading

Page 3: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

E-MSD is supported by grants from the Wellcome Trust, the EU (TEMBLOR, NMRQUAL and IIMS), CCP4, the BBSRC, the MRC and EMBL.

The BMRB is supported by NIH grant LM05799 from the National Library of Medicine.

PDBj is supported by grant-in-aid from the Institute for Bioinformatics Research and Development, Japan Science and Technology Agency (BIRD-JST), and the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

The RCSB PDB is supported by grants from the National Science Foundation, National Institute of General Medical Sciences, the Office of Science-Department of Energy, the National Library of Medicine, the National Cancer Institute, the National Center for Research Resources, the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes & Digestive & Kidney Diseases.

Markley, JL Henrick, K Berman, HM Nakamura, H

wwPDB and wwPDBAC members at EBI, Hinxton on 29 Sept, 2008

http://www.wwpdb.org

Page 4: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Development of other Databases and Services

Encyclopedia of Protein Structures, eProtS(Kinjyo, Kudo, & Ito）

Molecular of the Month, MoM(Goodsell & Kudo）Alignment of Sequence and

Structures. MAFFTash(Kato. Toh & Standley）

Homolog protein search,Sequence Navigator(Standley）

Similar fold search,Structure Navigator(Standley & Toh） Protein Folds Browser,

Protein Globe (Kinjo & Standley）

Page 5: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Search for Similar Surface, eF-seek (Kinoshita & Nakamura）

Electron Microscopy Navigator, EM-Navi (Suzuki）

Function Annotation from Folds and Sequences, SeSAW (Standley）

Ligand Binding Site Search,GIRAF (Kinjo）

Development of other Databases and Services

Protein Dynamics Database, ProMode (Wako & Endo)

Protein Molecular Surface Database, eF-site(Kinoshita & Nakamura）

Page 6: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Homology modeling for a target protein1) Introduction2) Search for homolog(s)3) Threading (3D-1D compatibility)4) Backbone modeling5) Side-chain modeling6) Structure optimization

Page 7: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Requirement for the homology modeling– Sequence information： 9.2 M (UniProt)– 3D Structure ： 59 K (wwPDB)

3D structural model can be made when any structure of the family protein is in DB.

・Total family number：about 30,000 (30% identity)・Total folds：about 2,000 (loose definition)

Principle– When sequence is similar, structure is similar.

Modeling procedure– Search homolog proteins.– Construct (multiple ) sequence alignment– Differences in the backbone and the side-

chains are modeled.

Homology modeling /Comparative modeling

D. Baker & A. Sali (2001) Science 294, 93-96.

A structural model of a target protein is constructed based on the homolog protein structure as a template, using the similarity of amino acid sequences

Page 8: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Swine Influenza A virus neuraminidase (NA) gene

NA sequence

AA sequence

Simple Example

Page 9: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

>2qwk chain-A: NEURAMINIDASE>Influenza A virus neuraminidase(NA) gene, complete cds. FJ981614

RDFNNLTKGLCTINSWHIYGKDNAVRIGEDSDVLVTREPYVSCDPDECRFYALSQGTTIRGKHSNGTIHDRSQYRALI:: .. : :: ::: :::: ::.: :::..:: : ::: . :.:: . :::::::.::: :: :.

---------LCPVSGWAIYSKDNSVRIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLM

SWPLSSPPTVYNSRVECIGWSSTSCHDGKTRMSICISGPNNNASAVIWYNRRPVTEINTWARNILRTQESECVCHNGV: :. :. .:::.: ..:: . :::: ..: ::::.: : ::. :: : .: :::::::::: : ::SCPIGEVPSPYNSRFESVAWSASACHDGINWLTIGISGPDNGAVAVLKYNGIITDTIKSWRNNILRTQESECACVNGS

CPVVFTDGSATGPAETRIYYFKEGKILKWEPLAGTAKHIEECSCYGERAEITCTCRDNWQGSNRPVIRIDPVAMTHTS: :.::: : : .:. . :::.: . . : :::::: . :::: ::::: ::::: . . . CFTVMTDGPSNGQASYKIFRIEKGKIVKSVEMNAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQ-NLEYQI

QYICSPVLTDNPRPNDPTVGKCNDPYPGNNNNGVKGFSYLDGVNTWLGRTISIASRSGYEMLKVPNALTDDKSKPTQG:::: .. ::::::: : : : : : ::::::: : :.::: :: :: :.::. ::. : . GYICSGIFGDNPRPNDKT-GSCG-PVSSNGANGVKGFSFKYGNGVWIGRTKSISSRNGFEMIWDPNGWTGTDNNFSIK

QTIVLNTDWSGYSGSFMDY—-WAEGECYRACFYVELIRGRPKEDKVWWTSNSIVSMCSSTEFLGQWDWPDGAKIEYFL: :: .::::::::. .: : ::.::::::::::. . ::: : .:.: : ::::: . .QDIVGINEWSGYSGSFVQHPELTGLDCIRPCFWVELIRGRPKENTI-WTSGSSISFCGVNSDTVGWSWPDGAELPF—

Ins/del

Page 10: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

2qwk A Swine NA model

Blue: 2qwk A

Red:Swine NA model

Page 11: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

>2qwk chain-A: NEURAMINIDASE>Influenza A virus neuraminidase(NA) gene, complete cds. FJ981614

RDFNNLTKGLCTINSWHIYGKDNAVRIGEDSDVLVTREPYVSCDPDECRFYALSQGTTIRGKHSNGTIHDRSQYRALI:: .. : :: ::: :::: ::.: :::..:: : ::: . :.:: . :::::::.::: :: :.

---------LCPVSGWAIYSKDNSVRIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLM

SWPLSSPPTVYNSRVECIGWSSTSCHDGKTRMSICISGPNNNASAVIWYNRRPVTEINTWARNILRTQESECVCHNGV: :. :. .:::.: ..:: . :::: ..: ::::.: : ::. :: : .: :::::::::: : ::SCPIGEVPSPYNSRFESVAWSASACHDGINWLTIGISGPDNGAVAVLKYNGIITDTIKSWRNNILRTQESECACVNGS

CPVVFTDGSATGPAETRIYYFKEGKILKWEPLAGTAKHIEECSCYGERAEITCTCRDNWQGSNRPVIRIDPVAMTHTS: :.::: : : .:. . :::.: . . : :::::: . :::: ::::: ::::: . . . CFTVMTDGPSNGQASYKIFRIEKGKIVKSVEMNAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQ-NLEYQI

QYICSPVLTDNPRPNDPTVGKCNDPYPGNNNNGVKGFSYLDGVNTWLGRTISIASRSGYEMLKVPNALTDDKSKPTQG:::: .. ::::::: : : : : : ::::::: : :.::: :: :: :.::. ::. : . GYICSGIFGDNPRPNDKT-GSCG-PVSSNGANGVKGFSFKYGNGVWIGRTKSISSRNGFEMIWDPNGWTGTDNNFSIK

QTIVLNTDWSGYSGSFMDY—-WAEGECYRACFYVELIRGRPKEDKVWWTSNSIVSMCSSTEFLGQWDWPDGAKIEYFL: :: .::::::::. .: : ::.::::::::::. . ::: : .:.: : ::::: . .QDIVGINEWSGYSGSFVQHPELTGLDCIRPCFWVELIRGRPKENTI-WTSGSSISFCGVNSDTVGWSWPDGAELPF—

Red: Active site residues surrounding Tamiflu

Page 12: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

2qwk A Swine NA model

Electrostatic molecular surfacesBlue: positive, Red: negative, yellow: hydrophobic

Page 13: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

>2qwk chain-A: NEURAMINIDASE>Influenza A virus neuraminidase(NA) gene, complete cds. FJ981614

RDFNNLTKGLCTINSWHIYGKDNAVRIGEDSDVLVTREPYVSCDPDECRFYALSQGTTIRGKHSNGTIHDRSQYRALI:: .. : :: ::: :::: ::.: :::..:: : ::: . :.:: . :::::::.::: :: :.

---------LCPVSGWAIYSKDNSVRIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLM

SWPLSSPPTVYNSRVECIGWSSTSCHDGKTRMSICISGPNNNASAVIWYNRRPVTEINTWARNILRTQESECVCHNGV: :. :. .:::.: ..:: . :::: ..: ::::.: : ::. :: : .: :::::::::: : ::SCPIGEVPSPYNSRFESVAWSASACHDGINWLTIGISGPDNGAVAVLKYNGIITDTIKSWRNNILRTQESECACVNGS

CPVVFTDGSATGPAETRIYYFKEGKILKWEPLAGTAKHIEECSCYGERAEITCTCRDNWQGSNRPVIRIDPVAMTHTS: :.::: : : .:. . :::.: . . : :::::: . :::: ::::: ::::: . . . CFTVMTDGPSNGQASYKIFRIEKGKIVKSVEMNAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQ-NLEYQI

QYICSPVLTDNPRPNDPTVGKCNDPYPGNNNNGVKGFSYLDGVNTWLGRTISIASRSGYEMLKVPNALTDDKSKPTQG:::: .. ::::::: : : : : : ::::::: : :.::: :: :: :.::. ::. : . GYICSGIFGDNPRPNDKT-GSCG-PVSSNGANGVKGFSFKYGNGVWIGRTKSISSRNGFEMIWDPNGWTGTDNNFSIK

QTIVLNTDWSGYSGSFMDY—-WAEGECYRACFYVELIRGRPKEDKVWWTSNSIVSMCSSTEFLGQWDWPDGAKIEYFL: :: .::::::::. .: : ::.::::::::::. . ::: : .:.: : ::::: . .QDIVGINEWSGYSGSFVQHPELTGLDCIRPCFWVELIRGRPKENTI-WTSGSSISFCGVNSDTVGWSWPDGAELPF—

Red: Active site residues surrounding Tamiflu

H274Y: Tamiflu resistant

Page 14: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

2qwk A

Electrostatic molecular surfacesBlue: positive, Red: negative, yellow: hydrophobic

H274E276

Page 15: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Precise Alignment3D-1D compatibility search (threading)

Procedure of Homology ModelingSearch for HomologFASTA, BLAST, psi-BLAST

Backbone modeling: Loopsloop search, conf. sampling

Side-chain modeling:Combinatorial problem

Dead End Elimination (DEE)

with high homology

with low homology

Page 16: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Homology modeling for a target protein1) Introduction2) Search for homolog(s)3) Threading (3D-1D compatibility)4) Backbone modeling5) Side-chain modeling6) Structure optimization

Goal of this Tutorial: To construct the homology model of hERG channel

Page 17: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Precise Alignment3D-1D compatibility search (threading)

Procedure of Homology ModelingSearch for HomologFASTA, BLAST, psi-BLAST

Backbone modeling: Loopsloop search, conf. sampling

Side-chain modeling:Combinatorial problem

Dead End Elimination (DEE)

with high homology

with low homology

Page 18: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Get amino-acid sequence of hERG channel from NCBI(http://www.ncbi.nlm.nih.gov/)

Page 19: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Page 20: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Get amino-acid sequence of hERG channel from UniProt(http://www.uniprot.org/)

Page 21: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Page 22: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Page 23: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Homology modeling for a target protein1) Introduction2) Search for homolog(s)3) Threading (3D-1D compatibility)4) Backbone modeling5) Side-chain modeling6) Structure optimization

Page 24: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Precise Alignment3D-1D compatibility search (threading)

Procedure of Homology ModelingSearch for HomologFASTA, BLAST, psi-BLAST

Backbone modeling: Loopsloop search, conf. sampling

Side-chain modeling:Combinatorial problem

Dead End Elimination (DEE)

with high homology

with low homology

Page 25: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

3D-1D compatibility search（Threading method）

3D Structure Library

Amino acid sequenceSeq-Struct compatibility

The amino acid sequence of a target protein is threaded on many known 3D structures, and the most compatible 3D structure is searched.

Page 26: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

(http://sysimm100.protein.osaka-u.ac.jp/sfas/)

(http://sysimm100.protein.osaka-u.ac.jp/tmp/SFAS16483/hERG_top.html)

Step2: Get homologs in PDB and have alignments with 3D modes.

Input your e-mail address

Page 27: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Result of SFAS: The best template is 2r9rB

Page 28: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Homology modeling for a target protein1) Introduction2) Search for homolog(s)3) Threading (3D-1D compatibility)4) Backbone modeling5) Side-chain modeling6) Structure optimization

Page 29: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Precise Alignment3D-1D compatibility search (threading)

Procedure of Homology ModelingSearch for HomologFASTA, BLAST, psi-BLAST

Backbone modeling: Loopsloop search, conf. sampling

Side-chain modeling:Combinatorial problem

Dead End Elimination (DEE)

with high homology

with low homology

Page 30: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Loop modeling: Modeling for deletion is easy, but for Insertion (in particular, with longer than 7 residues) is difficult.

・Loop Search method： the known loop fragments are used.

・Conformational search method： the most stable loop structure is searched from the possible candidates.

Page 31: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Small red points: 32 NMR str. (2AAS)

Large red: X-ray str. (8RAT)

α

γ β

α

β

Loop R8with 8 residues

Loop R12with 12 residues

RNase A from NMR (2AAS)

300K 700K

Random-walk in the Energy space

Watanabe, Y. S. et al. (2006) Biophys. 2, 1-12.

<RMSDn>α= 2.00 ARMSDx α = 1.65 A

<RMSDn>α= 0.93 ARMSDx α = 1.20 A

Modeling of a loop structure longer than 10 residues.

Page 32: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Homology modeling for a target protein1) Introduction2) Search for homolog(s)3) Threading (3D-1D compatibility)4) Backbone modeling5) Side-chain modeling6) Structure optimization

Page 33: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Precise Alignment3D-1D compatibility search (threading)

Procedure of Homology ModelingSearch for HomologFASTA, BLAST, psi-BLAST

Backbone modeling: Loopsloop search, conf. sampling

Side-chain modeling:Combinatorial problem

Dead End Elimination (DEE)

with high homology

with low homology

Page 34: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Ponder & Richards (1987) J. Mol. Biol. 193, 775-791.

b) Local stable conformations for individual residue from Statistics in PDB

Dunbrack & Karplus (1993) J. Mol. Biol. 230, 543-574.

Number lower/ upper lower/ upper +60° 180° -60°

Φ ψ χ-populationBackbone-dependent rotamer library for proteins

Side-chain modelinga) Local stable conformations for individual residue

at the energy minima

Page 35: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

c) Combinatorial approach (Monte Carlo method, GA, DEE, etc.)

Taylor, W. (1992) Nature 356, 478-480.

Side-chain modeling

Page 36: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

i = 2× × × ×× ××

×× × ×i = 3

i = 4

start

i = 1

c) Combinatorial approach

Algorithm of dead-end elimination (Desmet et al. Nature, 356, 539-542, 1992)Structural energy for side-chains of N-residues is described by the interaction energy between the backbone and the side-chain, E1, and the interaction energy between the side-chains, E2.

Dead-end elimination (DEE) method

Theorem: When the t’th rotamer (ti) of the i’th residue is found, satisfying the next equation for the r’throtamer (ri) of the i’th residue, then the global energy minimum conformation does not include the ri.

Using the above theorem, it is possible to find the global energy minimum conformation, gradually rejecting the non-probable side-chain structures that cannot be included in the global energy minimum conformation.

Page 37: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Acc

urac

y (%

)

a) White: Core regions. Black: all side-chains

b) Result of DEE for lysozyme. Blue: X-ray crystal structure, Yellow: DEE model structure, white: the coincident side-chain structures in between the crystal and the DEE model.

R. Tanimura et al. Protein Science, 3, 2358-2365, 1994

Page 38: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Homology modeling for a target protein1) Introduction2) Search for homolog(s)3) Threading (3D-1D compatibility)4) Backbone modeling5) Side-chain modeling6) Structure optimization

Page 39: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

Force FieldsBond stretches (1-2)

Angle bending (1-3)

Torsional rotation (1-4)

Improper torsion (1-4)

Electrostatic interaction (1-5)

Lennard-Jones interaction (1-5)

20

20

12 6

1 ( )2

1 ( )2

[1 cos( )]2

( )

[ ]

rbonds

angles

n

torsions

improper

i j

elec ij

ij ij

LJ ij ij

U k r r

k

V n

V improper torsion

q qr

A Br r

θ θ θ

φ δ

= −

+ −

+ + −

+

+

+ −

∑

∑

∑

∑

∑

∑

i

l

j

k

1-2

1-3

1-4

Stress in the 3D structural model is removed byMinimization/MD with the potential energy U.

Page 40: XXXVI Int. Congress of Phys. Sci. Tutorial-3 #2 Structural ...Jul 29, 2009 · Large red: X-ray str. (8RAT) α γ β α β Loop R8 with 8 residues Loop R12 with 12 residues RNase

http://swissmodel.expasy.org/ http://salilab.org/modeller/

New! Spannerhttp://www.pdbj.org/spanner/Constructed by Daron M. Standley (iFREC, Osaka U), Mieszko Lis (MIT), Haruki Nakamura (IPR, Osaka U)

Web site for homology modeling

Catalytic hydrogenation of α,β-unsaturated carboxylic acid

α β β α β β - University of Texas at Dallasbiewerm/5-applications.pdf · α + β " α + 0.97β " α - β α + 1.65β " α ‒ 0.68β " 1β " 0.68β The MO energy levels can

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BGRT: Relative Biologically Effectiveness (RBE) and Oxygen ...faculty.washington.edu/trawets/rds/pdf/uw23apr2010rbe(stewart).pdfbiological parameters: f i, (α/β)γ, (α/β) i Similar

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CHAPTER 13. RADIATION AND RADON GAS · 2013. 5. 28. · RaE 5.02 day RaF 138.3 day β 206 Pb stable β α α α α 214 RaB 26.8 min RaC 19.7 min RaC' 164 µs β α α,γ βγ α,γ

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Evaluating market consolidation in mobile …ec.europa.eu/.../eagcp_plenary_2015_session_1_1.pdfoct = α c + α t + β 1 Mkt_Str oct + β 2 Op_Char oct + ε oct where o = operator,

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An FPT Algorithm for Minimum Additive Spanner Problem · Minimum (α,β)-Spanner Problem isalsoﬁxed-parametertractable. WedeﬁnethePa-rameterized Minimum (α,β)-Spanner Problem