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

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 PD-B/P-DB/P-D-B Marc A. Marti-Renom Department of Biopharmaceutical Sciences University of California, San Francisco

ModDom 1phh (Oxydoreductase from Pseudomonas fluorescens )

9 8 3 4 5 6 7 1 2

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

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

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

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

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

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

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

Less significant {1,2}{3,4}{4,5} {5,6}{6,7}{7,8}{8,9} Threshold #1,2 Mammoth P-value Lp {1,2,3,4} 9 8 {6,7,8,9} 3 4 5 6 7 {5,6,7,8,9} 1 2 {3,4,5,6,7,8,9} Up {all} More significant

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

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

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

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

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

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

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

# 1 2 3 4 5 6 7 8 9 1 1 1 1 1 0 0 0 0 0 9 8 2 1 1 1 1 0 0 0 0 0 3 4 5 6 7 3 1 1 2 2 1 1 1 1 1 4 1 1 2 2 1 1 1 1 1 1 2 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 Threshold #3 MCL Cluster level (-I) 8 0 0 1 1 2 3 3 3 3 Stijn van Dongen (http://micans.org/mcl/) 9 0 0 1 1 2 3 3 3 3

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)

1phh 290-329 2.7Å 3.1 1phh 279-373 3.9Å 4.7 1hadB 72-111 1bke 310-410 Conservation Residue number 1phh (Oxydoreductase from Pseudomonas fluorescens )

1phh 1-213 3.0Å 8.1 1phh 1-319 3.6Å 9.8 1qjdA 125-379 1gerA 3-327 Conservation Residue number 1phh (Oxydoreductase from Pseudomonas fluorescens )

1phh 1-378 3.8Å 10.3 1phh 1-316 3.8Å 17.2 1feaC 2-464 1l9dB 2-364 Conservation Residue number 1phh (Oxydoreductase from Pseudomonas fluorescens )

1phh (Oxydoreductase from Pseudomonas fluorescens )

- Domains

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

Thresholds #1,2 � MAMMOTH P-Value (Lp, Up) High P-values � fewer partitions Threshold #3 � Cluster Level ( -I ) Low –I cluster value � fewer partitions

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

<dist to f(R)> -0.11 -0.10 -0.08 -0.09 5-46 1-84 47-84 85-192 1-239 193-23 85-239 9 1dhr_ (dihydropteridine reductase )

Non-redundant 234 chains % correct predictions

anthrax toxin protective antigen ModDom SCOP RMSD: 3.93Å over 40 residues Sequence Identity: 15.38% 1acc_ (180-226) 1cdq_ (all) human complement regulatory protein CD59.

canavalin from jack bean the human editing enzyme ADAR1

rat liver dihydropteridine reductase 1dhr_ 5-76 / 77-240 CD Database (NCBI) WcaG, Nucleoside-diphosphate-sugar epimerases Cell envelope biogenesis, outer membrane / Carbohydrate transport and metabolism

1 477 1f3iA Transposase 11 Transposase Tn5 PFam Islam et al ModDom PFam Islam et al ModDom

Authors SCOP ModDom 1bbhA 1phh

Authors SCOP ModDom 1gpb 1vsgA

Authors SCOP ModDom 1gpb 1vsgA

- Fragments Repetitions Swapping Complementarities

G-protein (1gotB) all - � � 7 bladed beta propeller domain 0.035 0.030 0.025 0.020 0.015 0.010 0.005 0

Ribosomal protein S6 (1ris) � + � � Ferrodoxin Like domain 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 1ee9A 17.9% id. 2.3Å 0 6timB 11.1% id. 2.6Å

Cytochrome C Peroxidase (2cyp) all- � � CCP-like domain 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 29/34 2.9Å 27/35 3.2Å

Barnase Domain-Swapping

Barnase Domain-Swapping

chymotrypsin inhibitor 2 1-37 | 38-64

chymotrypsin inhibitor 2 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 of 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.

� ModDom � Domains �� Fragments

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 http://www.salilab.org