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THE AXIOM. D atabanks + New tools = New insights. S imple A tom D epth I ndex C alculator. protein fold barcoding CATH – ADAPT…. -1. SADIC: a new tool to analyze atom depth. Digging inside objects to discover their origins. Birth of the Earth. protein folding. 2D.
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THE AXIOM Databanks + New tools = Newinsights SimpleAtomDepthIndexCalculator proteinfoldbarcoding CATH – ADAPT… -1
SADIC: a newtooltoanalyzeatomdepth Digging inside objectstodiscovertheirorigins Birth of the Earth protein folding
2D HEWL 4lzt atom depth atomdepthcalculatedas the distancewith: the closestexternalwater* the closest dot of the water accessiblesurface* the closestsurfaceexposedatom* *Chakravarty S, Varadarajan R. Residue depth: a novelparameterfor the analysisofproteinstructure and stability. StructureFoldDes. 1999 7:723-732 *Pintar A, Carugo O, Pongor S.Atomdepthas a descriptorof the proteininterior. Biophys J. 2003 84:2553-2561.
2D Calculation of exposed volumes HEWL 4lzt Daniele Varrazzo, Andrea Bernini1, Ottavia Spiga, Arianna Ciutti, Stefano Chiellini,Vincenzo Venditti, Luisa Bracci and Neri Niccolai. Three-dimensional Computation of Atomic Depth in Complex Molecular Structures Bioinformatics 2005 21:2856-2860 atom depth 3D 2D
atom depth 3D Calculation of exposed volumes Daniele Varrazzo, Andrea Bernini1, Ottavia Spiga, Arianna Ciutti, Stefano Chiellini,Vincenzo Venditti, Luisa Bracci and Neri Niccolai. Three-dimensional Computation of Atomic Depth in Complex Molecular Structures Bioinformatics 2005 21:2856-2860 HEWL 4lzt
atom depth 3D Calculation of exposed volumes Depth index: Di,r= 2Vi,r/ V 0,r where Vi,ris the exposed volume of a sphere of radius r centered on atom i of the molecule and V0,ris the exposed volume of the same sphere when centered on an isolated atom the sphere radius r should have the biggest value which makes Vi = 0 for the most buried atom Daniele Varrazzo, Andrea Bernini1, Ottavia Spiga, Arianna Ciutti, Stefano Chiellini,Vincenzo Venditti, Luisa Bracci and Neri Niccolai. Three-dimensional Computation of Atomic Depth in Complex Molecular Structures Bioinformatics 2005 21:2856-2860 HEWL 4lzt
atom depth 3D vs 2D Thr 47 α carbon Di,9 = 1.59 Ile 58 α carbon Di,9 = 0.13 Trp 28 α carbon Di.9 = 0.03 28 58 47 HEWL 4lzt
3D atomdepthanalysis Di from PDB ID 1UBQ http://www.sbl.unisi.it/prococoa/
SBL BioinformaticsProjects • Projects SADIC correlated: • 1. folddependentaacompositionsofproteincores; • 2. towardsi-SADIC. • ---------------------------------------------------- • Projects SADIC uncorrelated: • 1. systematicanalysisof PPI
Dianalysisofproteinatoms • definingstruturallayers in protein 3D structures • eachstruturallayerincludesatomswithsimilar Di’s • fast and accurate analysisofaacontentofstructurallayers
Dianalysisofproteinatoms 3 VTR (chitinolyticenzyme 572 aa)
3D atomdepthanalysis Dimax Dimax Dimax N 0.19 CA 0.30 C 0.25 O 0.23 CB 0.50 CG 0.68 CD 0.91 CE 1.11 NZ 1.29 K63 N 0.10 CA 0.05 C 0.11 O 0.18 CB 0.02 CG 0.02 CD1 0.02 CD2 0.00 L43 http://www.sbl.unisi.it/prococoa/ N 0.38 CA 0.52 C 0.50 O 0.52 CB 0.76 CG 0.95 CD 1.17 OE1 1.24 OE2 1.24 E24 from PDB ID 1UBQ
Dimaxanalysisofproteinresidues • definingaaoccupancy in proteinstruturallayers • eachstruturallayerincludesresidueswithsimilarDimax’s • fast and accurate analysisofaadistribution in proteinstructures
Dimaxanalysisofproteinsingles quite a fewproteinsliketo stay single (at least in the crystalline state) -9 Bioinformatiha 2, Firenze 18 ottobre
a database ofproteinsingles Experimental Method: X-RAY (79,770) Chain Type: Protein (74,456) Only 1 chain in asym. unit: (28,803) Oligomeric state: 1 (21,193) Number of Entities: 1 (3,517) Homologue Removal @ 95% identity (2,410) • DOOPS: • 2,410 proteins in the dataset • 4,657,574 atoms • 589,383 residues
a database ofproteinsingles • Swiss-Prot: 540,958 proteins in the dataset (192 Maa) • DOOPS: • 2,410 proteins in the dataset • 4,657,574 atoms • 589,383 residues 0 2000 1000
Dimaxanalysisofproteincores • 2,410 proteins; 4,657,574 atoms; 589,383 residues • DOOPS: • calculationof % amino acid content in L0 • the first quantitative analysisof a largearrayofproteincores! coreaaifDimax< 0.2 • ~20 % of total molecular volume ΣDOOPS aa(L0) = 106,088 (from 2410 proteins)
: • Dianalysisofproteincores • foldingcluesfromaacorecomposition?
: • Dianalysisofproteincores • foldingcluesfromaacorecomposition? DOOPS + CATH selectedArchitectures with ≥ 10 PDB files # ( ) domain
Towardsproteinfoldingbarcodes aa % averagevalue (av) av + σ av + 2σ av - σ av - 2σ Diof 173,536 CATH domains 28 h, 5’ (average comp. time 1.72 s/domain) Calculationsperformed on 6 cores 990X CPU based computer Cys Leu Phe Val Ala CATH-ADAPT CATH - atomdepthassistedproteintomography fourlayer sandwich alpha horseshoe ribbon trefoil PDB ID 2IMH(A01) PDB ID 3CKC(A02) PDB ID 1UZK(A01) PDB ID 1RG8(A00)
Towardsproteinfoldingbarcodes Puttingthe proteinuniverse in order
Towardsproteinfoldingbarcodes Puttingthe proteinuniverse in order
towardsi-SADIC (implemented SADIC)
towardsi-SADIC (implemented SADIC) H/D exchange rate profiles
towardsi-SADIC (implemented SADIC) H/D exchange rate profiles D D D D D D D D D D D D D D
towardsi-SADIC (implemented SADIC) H/D exchange rate profiles
towardsi-SADIC (implemented SADIC) H/D exchange rate profiles
towardsi-SADIC (implemented SADIC) H/D exchange rate profiles
H/D exchange rate profiles 2D atomdepthor 3D atomdepth dnwi= or atomdistancewith the nearest water molecule Di,9 = or atomdepthindexwith a probe od radius 9 Å data from Pedersen TG, Thomsen NK, Andersen KV, Madsen JC, Poulsen FM. Determination of the rate constants k1 and k2 of the Linderstrom-Lang model for protein amide hydrogen exchange. A study of the individual amides in hen egg-white lysozyme. J Mol Biol. 1993 230(2):651-660.
H/D exchange rate profiles iSADICatomdepth 3D atomdepth Di,9 = or atomdepthindexwith a probe od radius 9 Å iDi,9 = aDi,9 + bASAi cDi,9 + dDnwi data from Pedersen TG, Thomsen NK, Andersen KV, Madsen JC, Poulsen FM. Determination of the rate constants k1 and k2 of the Linderstrom-Lang model for protein amide hydrogen exchange. A study of the individual amides in hen egg-white lysozyme. J Mol Biol. 1993 230(2):651-660.
H/D exchange rate profiles iSADICatomdepth3D atomdepth iDi,9 = aDi,9 + bASAi cDi,9 + dDnwi
protein-protein interface analysis biological vs crystallographicinterfaces
crystallographicdimers biologicaldimers
N ARG CA ARG C ARG O ARG CB ARG CG ARG CD ARG NE ARG CZ ARG NH1 ARG NH2 ARG H ARG HA ARG HB2 ARG HB3 ARG HG2 ARG HG3 ARG HD2 ARG HD3 ARG HE ARG HH11 ARG HH12 ARG HH21 ARG HH22 ARG N LYS CA LYS C LYS O LYS CB LYS CG LYS CD LYS CE LYS NZ LYS H LYS HA LYS HB2 LYS HB3 LYS HG2 LYS HG3 LYS HD2 LYS HD3 LYS HE2 LYS HE3 LYS HZ1 LYS HZ2 LYS HZ3 LYS vs