Advanced in silico Drug Design KFC/ADD Structural Biology Tools
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1 Advanced in silico Drug Design KFC/ADD Structural Biology Tools Karel Berka, Ph.D., Jindřich Fanfrlík, Ph.D. Martin Lepšík, Ph.D., Pavel Polishchuk, Ph.D. UP Olomouc,
2 Motto Function of protein is given by its structure. 2
3 prof. Janet Thornton Use of Protein 3D Structure
4 STRUCTURAL DATABASES
5 Century of Life Science Data Protein sequences Uniprot R. Svobodová-Vařeková habilitation lecture 2016
6 Databases, you ask? htttp:// For more complete list of structural databases please refer to
7 PDB Protein Data Bank
8 PDB Statistics Structures ( ) X-ray NMR 9108 EM 380 (on rise) Proteins NA 2312 Protein/NA 3331 Most structures: organism-thermus thermophilus (4751) gene source Homo Sapiens (20127) R A (26000) Software CNS (25276) EC Lysozyme (1150) Residues (30000) Journal J.Mol.Biol. (9247) 1st Nov
9 PDB = Primary database Structures of proteins, nucleic acids, sugars, ligands, Links to other databases (Uniprot) PDBe J. Koča et al., Structural Bioinformatics Tools for Drug Design, SpringerBriefs in Biochemistry and Molecular Biology, DOI / _3
10 J. Koča et al., Structural Bioinformatics Tools for Drug Design, SpringerBriefs in Biochemistry and Molecular Biology, DOI / _3 RCSB PDB
11 Other Structural DBs Classification CATH Domain classification of structures Pfam Classification of sequence families Flexibility and disorder PDB FLEX Intrinsic flexibility in proteins DisProt Database of Protein Disorder Pocketome Encyclopedia of ensembles of druggable binding sites Detailed biomacromolecules OPM Orientations of proteins in membranes NDB Nucleic Acids Database GFDB Glycan Fragment Database For more complete list of structural databases please refer to J. Koča et al., Structural Bioinformatics Tools for Drug Design, SpringerBriefs in Biochemistry and Molecular Biology, DOI / _3
12 PROTEIN FUNCTION DETECTION
13 Function Definition EC enzyme classification (4 levels of detail) Oxidoreductases (EC 1) substrate is a donor of hydrogen or electrons what substrate acceptor-type only enzymes 1 enzyme more functions methylenetetrahydrofolate dehydrogenase/cyclohydrolase (EC and EC ) GO - Gene Ontology genome annotation more generic Biological process generic (cell growth) specific (glycolysis) Molecular function generic (enzyme) specific (hexokinase) Cell compartmentalisation where it works (ER, cytosol) catalytic domain NADPH-binding domain
14 Function Search - Possibilities Sequence below 40% identity is function less conserved (exception CYP) Fold matching structure alignment (DALI, FATCAT) against annotated structural db (CATH, SCOP) 3D motives active site position (TESS, PDBSiteScan, PatternQuery) Active sites geometric similarity (SURFNET) physical properties (SURF S UP!, SiteEngine)! same substrate can have multiple sites ATP
15 Function Search Possibilities II Phylogenetic analysis search for conserved residues by multiple alignement (ConSurf) DNA binding Helix-turn-helix motiv (HTHquery) Ligands similar sites as in other crystals in PDB (PDBsum, MSDsite) Channel anotation Towards active site substrate channelling (Caver, MOLE)
16 Function Search - ProFunc
17 PATTERNS
18 Pattern Detection: Why? R. Svobodová-Vařeková habilitation lecture 2016
19 Pattern Detection: Approaches Software: OpenStructure, Protein segment finder, PatternQuery* *Sehnal, Pravda, Svobodová et al., Nucl. Acids Res. (2015)
20 Pattern Detection Example sugar binding site from Pseudomonas aeruginosa lectin Results (38 entries from PDB): Pseudomonas aeruginosa (27 entries) or its synthetic (2 entries) Burkholderia cenocepacia (4 entries) Ralstonia solanacearum (2 entries) Chromobacterium violaceum (2 entries) Bacillus subtilis (1 entry) R. Svobodová-Vařeková habilitation lecture 2016
21 ACTIVE SITE
22 Determines function Active Site Searchable by different approaches: Size and shape Large (protein-protein, ev. protein-dna) PPI-PRED small (clefts, ligandy) - On surface, or deep-inside (channels) SURFNET, PocketFinder, Q-SiteFinder Phys chem properties hydrophobic patches charged surfaces Residue conservation evolution trace method ConSurf meta methods aka ProFunc
23 SAS a SES Cleft search solvent accessible surface solvent excluded surface Cleft search Pocket-Finder Slicing of receptor in several orientations Closed spaces cavities Partially closed pockets QSiteFinder grid search with generic probe (methan)
24 Channel Detection important role in biomolecular function codetermine specificity
25 Channel Detection: Caver Caver Dijkstra s algorithm for optimal pathway search on grid or on Voronoi mesh Petrek, M. et al - CAVER: a new tool to explore routes from protein clefts, pockets and cavities, BMC Bioinformatics 2006, 7:316 Beneš, P. et al. - CAVER 2.1 software, 2010.
26 Channel Detection: MOLE MOLE Atoms maps => Voronoi diagram Petrek M., Kosinova P., Koca J., Otyepka M.: MOLE: A Voronoi Diagram-Based Explorer of Molecular Channels, Pores, and Tunnels. Structure (2007) 15,
27 Channel Detection: MOLE 2.0 * Sehnal, Svobodová, et al., J. Cheminf. (2013) ** Berka,..., Svobodová, et al., Nucl. Acids Res. (2012)
28 Channel Detection example Cytochrome P450 3A4 - channel analysis via MOLE 2: Results: Channels from active site: the solvent channel (blue) product egress the channel 2a (red) and 2e (red) - hydrophobic substrate binding and access PDBID: 1tqn
29 Anatomy of Channels Methodology: Analysis of all the enzyme structures from PDB (4.306 structures) Calculation of their properties via MOLE Statistical analysis Pravda L, Berka K, Svobodová Vařeková R, Sehnal D, Banáš P, Laskowski RA, Koča J, Otyepka M: Anatomy of enzyme channels. BMC Bioinf., 15(1), 379, 2014.
30 Anatomy of Channels Results*: 64% of enzymes have at least one channel Median channel length was 27.7 Å Most of the channels are polar An average channel is lined by 2 negative and 2 positive AAs gating AAs enriched: Pravda L, Berka K, Svobodová Vařeková R, Sehnal D, Banáš P, Laskowski RA, Koča J, Otyepka M: Anatomy of enzyme channels. BMC Bioinf., 15(1), 379, 2014.
31 SPECIALTY SERVERS MEMBRANE PROTEINS, DISORDER
32 Membrane Proteins > 60% drug targets are membrane bound Alas not much membrane protein structures are known Di Meo F, Fabre G, Berka K, Ossman T, Chantemargue B, Paloncýová M, Marquet P, Otyepka M, Trouillas P: In Silico Pharmacology: Drug Membrane Partitioning and Crossing. Pharmacol. Res., 111, , 2016.
33 Cell Membranes Data from Van Meer, G.; Voelker, D. R.; Feigenson, G. W.; Manuscript, A. Membrane Lipids: Where They Are and How They Behave. Nat. Rev. Mol. Cell Biol. 2008, 9,
34 Orientations of Proteins in Membranes protein = rigid body OPM server Optimization of protein orientation in anisotropic implicit membrane model + membrane composition photosystem II
35 Disorder (Invisible) no structures estimates B-faktor in Xray, NMR ensemble, DISOPRED intristically disordered proteins no need of structure to function Regulation functions: molecular recognition (promiscuitous) molecular assembly (viral kapsids) protein modification entropic chain activities (entropic hourglasses)
36 TAKE HOME MESSAGE
37 Take Home Message There is an enormous amount of information available Primary databases - PDB and Uniprot Structure defines function Active site can have quite often channels Membrane proteins are one of the most important groups Disorder is also important especially in regulatory proteins (protein-protein interactions)
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