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Modeling of proteins and complexes High resolution Low resolution - - PowerPoint PPT Presentation

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Modeling of proteins and complexes High resolution Low resolution Modeling of domains Modeling of complexes Modeling of proteins and complexes High resolution Low resolution Modeling of domains Modeling of complexes Fragmenting the PDB

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Modeling of proteins and complexes

High resolution Modeling of domains Low resolution Modeling of complexes

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Modeling of proteins and complexes

High resolution Modeling of domains Low resolution Modeling of complexes

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Marc A. Marti-Renom

Department of Biopharmaceutical Sciences University of California, San Francisco

Fragmenting the PDB

PD-B/P-DB/P-D-B

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1phh (Oxydoreductase from Pseudomonas fluorescens)

ModDom

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4 5 6 9 7 8 2 3 1

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4 5 6 9 7 8 2 3 1

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9}

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4 5 6 9 7 8 2 3 1

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} {1,2,3,4}

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4 5 6 9 7 8 2 3 1

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} {1,2,3,4} {6,7,8,9}

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4 5 6 9 7 8 2 3 1

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} {1,2,3,4} {6,7,8,9} {5,6,7,8,9}

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4 5 6 9 7 8 2 3 1

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} {1,2,3,4} {6,7,8,9} {5,6,7,8,9} {3,4,5,6,7,8,9}

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4 5 6 9 7 8 2 3 1

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} {1,2,3,4} {6,7,8,9} {5,6,7,8,9} {3,4,5,6,7,8,9} {all}

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4 5 6 9 7 8 2 3 1

More significant Less significant

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} {1,2,3,4} {6,7,8,9} {5,6,7,8,9} {3,4,5,6,7,8,9} {all}

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4 5 6 9 7 8 2 3 1

More significant Less significant

{1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} {1,2,3,4} {6,7,8,9} {5,6,7,8,9} {3,4,5,6,7,8,9} {all}

Threshold #1,2 Mammoth P-value Lp

Up

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{1,2,3,4} {6,7,8,9} {5,6,7,8,9} {3,4,5,6,7,8,9}

4 5 6 9 7 8 2 3 1

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# 1 2 3 4 5 6 7 8 9 1 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 0 7 0 0 0 0 0 0 0 0 0 8 0 0 0 0 0 0 0 0 0 9 0 0 0 0 0 0 0 0 0

4 5 6 9 7 8 2 3 1

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4 5 6 9 7 8 2 3 1

# 1 2 3 4 5 6 7 8 9 1 1 1 1 1 0 0 0 0 0 2 1 1 1 1 0 0 0 0 0 3 1 1 1 1 0 0 0 0 0 4 1 1 1 1 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 0 7 0 0 0 0 0 0 0 0 0 8 0 0 0 0 0 0 0 0 0 9 0 0 0 0 0 0 0 0 0

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4 5 6 9 7 8 2 3 1

# 1 2 3 4 5 6 7 8 9 1 1 1 1 1 0 0 0 0 0 2 1 1 1 1 0 0 0 0 0 3 1 1 1 1 0 0 0 0 0 4 1 1 1 1 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 1 1 1 1 7 0 0 0 0 0 1 1 1 1 8 0 0 0 0 0 1 1 1 1 9 0 0 0 0 0 1 1 1 1

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4 5 6 9 7 8 2 3 1

# 1 2 3 4 5 6 7 8 9 1 1 1 1 1 0 0 0 0 0 2 1 1 1 1 0 0 0 0 0 3 1 1 1 1 0 0 0 0 0 4 1 1 1 1 0 0 0 0 0 5 0 0 0 0 1 1 1 1 1 6 0 0 0 0 1 2 2 2 2 7 0 0 0 0 1 2 2 2 2 8 0 0 0 0 1 2 2 2 2 9 0 0 0 0 1 2 2 2 2

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4 5 6 9 7 8 2 3 1

# 1 2 3 4 5 6 7 8 9 1 1 1 1 1 0 0 0 0 0 2 1 1 1 1 0 0 0 0 0 3 1 1 2 2 1 1 1 1 1 4 1 1 2 2 1 1 1 1 1 5 0 0 1 1 2 2 2 2 2 6 0 0 1 1 2 3 3 3 3 7 0 0 1 1 2 3 3 3 3 8 0 0 1 1 2 3 3 3 3 9 0 0 1 1 2 3 3 3 3

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# 1 2 3 4 5 6 7 8 9 1 1 1 1 1 0 0 0 0 0 2 1 1 1 1 0 0 0 0 0 3 1 1 2 2 1 1 1 1 1 4 1 1 2 2 1 1 1 1 1 5 0 0 1 1 2 2 2 2 2 6 0 0 1 1 2 3 3 3 3 7 0 0 1 1 2 3 3 3 3 8 0 0 1 1 2 3 3 3 3 9 0 0 1 1 2 3 3 3 3

4 5 6 9 7 8 2 3 1

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# 1 2 3 4 5 6 7 8 9 1 1 1 1 1 0 0 0 0 0 2 1 1 1 1 0 0 0 0 0 3 1 1 2 2 1 1 1 1 1 4 1 1 2 2 1 1 1 1 1 5 0 0 1 1 2 2 2 2 2 6 0 0 1 1 2 3 3 3 3 7 0 0 1 1 2 3 3 3 3 8 0 0 1 1 2 3 3 3 3 9 0 0 1 1 2 3 3 3 3

Threshold #3 MCL Cluster level (-I)

4 5 6 9 7 8 2 3 1

Stijn van Dongen (http://micans.org/mcl/)

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Thresholds #1,2 MAMMOTH P-Value (Lp, Up)

High P-values fewer partitions

Threshold #3 Cluster Level (-I)

Low –I cluster value fewer partitions

Applied to the ~40,000 chains in PDB (Dec 2002)

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1phh (Oxydoreductase from Pseudomonas fluorescens)

1phh 290-329 2.7Å 3.1 1hadB 72-111 1phh 279-373 3.9Å 4.7 1bke 310-410

Residue number

Conservation

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1phh 1-213 3.0Å 8.1 1qjdA 125-379 1phh 1-319 3.6Å 9.8 1gerA 3-327

1phh (Oxydoreductase from Pseudomonas fluorescens) Residue number

Conservation

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1phh 1-378 3.8Å 10.3 1feaC 2-464 1phh 1-316 3.8Å 17.2 1l9dB 2-364

1phh (Oxydoreductase from Pseudomonas fluorescens) Residue number

Conservation

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1phh (Oxydoreductase from Pseudomonas fluorescens)

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  • Domains
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2163 chains from Islam et al. 1995 569 Non-redundant <2Å && <30aa diff. Divide randomly into two sets Remove of incomplete or obsolete entries.

FINAL: Training set 242 chains Testing set 234 chains

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Thresholds #1,2 MAMMOTH P-Value (Lp, Up)

High P-values fewer partitions

Threshold #3 Cluster Level (-I)

Low –I cluster value fewer partitions

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R = Volume/ASA Domain max(<dist f(R)>)

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1dhr_ (dihydropteridine reductase ) 193-23 9 85-192 47-84 5-46 85-239 1-84 1-239

  • 0.11
  • 0.10
  • 0.08
  • 0.09

<dist to f(R)>

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Non-redundant 234 chains

% correct predictions

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1acc_ (180-226) 1cdq_ (all)

RMSD: 3.93Å over 40 residues Sequence Identity: 15.38%

anthrax toxin protective antigen

ModDom SCOP

human complement regulatory protein CD59.

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canavalin from jack bean

the human editing enzyme ADAR1

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1dhr_ 5-76 / 77-240

rat liver dihydropteridine reductase

CD Database (NCBI) WcaG, Nucleoside-diphosphate-sugar epimerases Cell envelope biogenesis, outer membrane / Carbohydrate transport and metabolism

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ModDom

1

477

1f3iA PFam Transposase 11 Transposase Tn5

PFam Islam et al

Islam et al

ModDom

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1bbhA 1phh Authors SCOP ModDom

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1gpb Authors SCOP ModDom 1vsgA

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1gpb Authors SCOP ModDom 1vsgA

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  • Fragments

Repetitions Swapping Complementarities

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G-protein (1gotB) all- 7 bladed beta propeller domain

0.005 0.010 0.015 0.020 0.025 0.030 0.035

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Ribosomal protein S6 (1ris) + Ferrodoxin Like domain

0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40

6timB 11.1% id. 2.6Å 1ee9A 17.9% id. 2.3Å

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Cytochrome C Peroxidase (2cyp) all- CCP-like domain

0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40

27/35 3.2Å 29/34 2.9Å

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Barnase Domain-Swapping

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Barnase Domain-Swapping

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1-37 | 38-64 chymotrypsin inhibitor 2

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1-37 | 38-64 1-40 | 41-64

  • Neira JL, Davis B, Ladurner AG, Buckle AM, Gay GP, Fersht AR. 1996. Towards the complete structural characterization of a protein

folding pathway: the structures of the denatured, transition and native states for the association/folding of two complementary fragments

  • f cleaved chymotrypsin inhibitor 2. Direct evidence for a nucleation-condensation mechanism. Fold Des 1:189-208.
  • Ladurner AG, Itzhaki LS, de Prat GG, Fersht AR. 1997. Complementation of peptide fragments of the single domain protein

chymotrypsin inhibitor 2. J Mol Biol 273:317-329.

chymotrypsin inhibitor 2

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ModDom Domains Fragments

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http://www.salilab.org

Acknowledgments

Andrej Sali David Katz Mark Peterson Angel Ortiz

Frank Alber Fred Davis Damien Devos Narayanan Eswar Rachel Karchin Mike Kim Libusha Kelly Dmitry Korkin

  • M. S. Madhusudhan

Ursula Pieper Andrea Rossi Min-yi Shen Maya Topf