SiteEngine: Functional Sites Structural Search Engine

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Presentation transcript:

SiteEngine: Functional Sites Structural Search Engine Shulman-Peleg A., Nussinov R. and Wolfson H. J. Recognition of Functional Sites in Proteins Structures, J. Mol. Biol. 339(3), 607 633.

SiteEngine Recognizes surface regions of one protein that resemble a specific binding site of another. Measures the similarity of physico-chemical and geometrical properties. SiteEngine Input Output Complete protein Binding site 3D transfor-mation. Similarity Score

Biological Motivation Potential ligands and ligand fragments. Prediction of side effects. Inferring a function of a novel protein. Biological classifications.

3-D Database Searches Application III: Query: a complete protein DB: binding sites Application I: Query: a binding site DB: complete proteins Application II: Query: a binding site DB: binding sites DB of complete proteins DB of binding sites

- Hydrogen bond acceptor - Hydrogen bond donor - donor/acceptor - Hydrophobic Aliphatic - Aromatic (PI) contacts Representation III. The solid angle shape function (Connolly 83’) is calculated at the center of each physico-chemical patch. I. Each amino acid is represented by a set of its physico-chemical properties (Schmitt 02’). II. Each property creates a physico-chemical patch on the protein surface.

Recognition of adenine binding sites A benchmark data set (121 proteins) was searched for binding sites similar to that of cAMP-dependent protein kinase (1atp). Ranked 7 was the an ATP binding site of a structurally different “hypothetical” protein MJ0577 from Methanococcus jannaschii. - cAMP-dependent protein kinase (1atp) - MJ0577 Structural genomics protein (1mjh, ranked 7) *The ligands are displayed for verification only!

Searching the Entire PDB 1. Searching the ASTRAL dataset with the adenine binding site of c-AMP dependent protein kinase (1atp). Replication factor C (1iqp, purple). Ranked 19. D-Ala-D-Ala ligase (1iow). Ranked 31. 2. Searching the ASTRAL dataset with the estradiol binding site of sex hormone-binding globulin (1lhu). Tropinone reductase (2ae2). Ranked 43. Estrogen sulfotransferase (1aqu). Ranked 38.

Web Server http://bioinfo3d.cs.tau.ac.il/SiteEngine

Matching Triplets of pseudo-centers are hashed and matched. Each pair of triangles with similar side lengths and similar nodes defines a candidate transformation. Hash Table Key = (index, ) Index = PII ALI Transformation Complexity:

Hierarchical Scoring Comparison of the shapes and physico-chemical properties of the surfaces. 1. Low-Resolution scoring Based on a sparse representation by chemically important surface points (centers of physico-chemical surfaces patches). 2. High-Resolution scoring More precise calculations based on high density sampling of the surfaces.

Interacting Triangles Interacting triangle (I-triangle) is a triplet of functional groups (pseudocenters) of one molecule that is recognized to form three interactions with the other molecule. - Hydrogen bond acceptor - Hydrogen bond donor - Donor/acceptor - Hydrophobic Aliphatic - Aromatic (PI) contacts

Hashing and Matching of I-triangles

Figure 1: SiteEngine Recognition of an ATP binding site similar to that of cAMP-dependent protein kinase (1atp- , ATP- ) in the structure of a Structural Genomics protein MJ0577 (1mjh- , ATP- ). - Hydrogen bond acceptor - Hydrogen bond donor - Donor/acceptor - Hydrophobic Aliphatic - Aromatic (PI) contacts Figure 2: I2I-SiteEngine Alignment of the interfaces formed by Subtilisin Thermitase with Eglin C (3tec) and B-trypsin with BPTI inhibitor (2ptc). .

Recognition of estradiol binding sites The benchmark data set (121 proteins) was searched for binding sites similar to that of 1lhu (Sex hormone-binding globulin). All 12 proteins which are in complex with estradiol (EST) were within the 30 best solutions. (A) (B) proteins from the data set 1qkt (A), 1fds (B). - ligands and active sites (dots) from : 1qkt (A), 1fds (B). - ligand and active site (dots) from 1lhu (A) – highest ranking (rank 2) EST binding site of 1qkt - estrogen receptor alpha (B) – lowest ranking (rank 29) EST binding site of 1fds - 17beta hydroxysteroid dehydrogenase *The ligands are displayed for verification only!