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Protein docking is used to check the structure, position and orientation of a protein when it interacts with small molecules like ligands. Protein receptor-ligand motifs fit together …

Protein docking is used to check the structure, position and orientation of a protein when it interacts with small molecules like ligands. Protein receptor-ligand motifs fit together tightly, and are often referred to as a lock and key mechanism. There are both high specificity and induced fit within these interfaces with specificity increasing with rigidity. The foremost thing that we need to start with a docking search is the sequence of our protein of interest. (Halperin et al., 2002).
Protein-protein interactions occur between two proteins that are similar in size. The interface between the two molecules tends to be flatter and smoother than those in interfaces of these interactions do not have the ability to alter protein-ligand interactions. Protein-protein interactions are usually more rigid, the conformation in order to improve binding and ease movement. (Smith and Sternberg, 2002).
The process of drug development has revolved around a screening approach, as nobody knows which compound or approach could serve as a drug or therapy. Such almost blind screening approach is very time-consuming and laborious. The goal of structure-based drug design is to find chemical structures fitting in the binding pocket of the receptor. Based on the three-dimensional structure of the target protein, it can automatically build ligand molecules within the binding pocket and subsequently screen them (Weil et al., 2004).
A homology model of the housefly voltage-gated sodium channel was developed to predict the location of binding sites for the insecticides fenvalerate, a synthetic pyrethroid, and DDT, an early generation organochlorine. The model successfully addresses the state-dependent affinity of pyrethroid insecticides. (O’Reilly et al., 2006).

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  • 1. Protein Docking Rajendra Kumar
  • 2. Proteins Are… The functional units of the cell Polymers of amino acids Maintain a key role in intra and intercellular processes Maintain the control functions as Enzymes Characteristic elements are : carbon,hydrogen,oxygen,nitrogen
  • 3. Definition  To place a ligand into the binding site of a protein in the appropriate manner for optimal interactions with a receptor proteinGoal: To be able to search a database of molecular structures and retrieve all molecules that can interact with the query structure
  • 4. Protein-protein Docking Aim: predict the structure of a protein complex from its partners + Complex Monomers (James meiler,2007)
  • 5. Types of Docking studies Protein-Protein Docking Both molecules usually considered rigid  6 degrees of freedom  Search space and the energetics of possible binding conformations Protein-Ligand Docking  Flexible ligand, rigid-receptor  Reduce flexible ligand to rigid fragments connected by one or several hinges, or search the conformational space using molecular dynamics
  • 6. Rigid Vs Flexible docking Rigid Body Docking:  No modification in bond angles, lengths & torsion angles of the components Flexible Docking :  Takes in to the conformational changes
  • 7. Protein docking is the computational determination of protein complexstructure from individual protein structures. (Smith and Sternberg, 2002)
  • 8. Interactions lead to … Ligand binds to the active site of protein Binding leads to conformational changes in protein Conformational changes thermodynamically most stable Lowest Gibb’s energy
  • 9. Protein –Protein interaction Thermodynamics (Smith and Sternberg, 2002)
  • 10. Why docking is important? It is of extreme relevance in cellular biology, where function is accomplished by proteins interacting with themselves and with other molecular components It is the key to rational drug design: The results of docking can be used to find inhibitors for specific target proteins and thus to design new drugs.
  • 11. Basic Requirements For Docking Structure of protein of interest should be known X-ray Crystallography NMR Spectroscopy
  • 12. X-Ray Diffraction The spacing of atoms in a crystal lattice can be determined by measuring the locations and intensities of spots produced on photographic film. x-ray analysis of sodium chloride crystals shows that Na and Cl ions are arranged in a simple cubic lattice. X – rays, wavelengths in the range of 0.7 to 1.5 Å (0.07 to 0.15 nm). ( Hubbard, 2006)
  • 13. cont..( Hubbard, 2006)
  • 14. ( Hubbard, 2006)
  • 15. Nuclear Magnetic Resonance Modern NMR techniques are being used to determine the structures of larger macromolecules. NMR is based on nuclear spin angular momentum. Only certain atoms, including 1H, 13C, 15N, 19F,and 31P, possess the kind of nuclear spin that gives rise to an NMR signal. (James,1998)
  • 16. (James, 1998)
  • 17. Why this is difficult? Both molecules are flexible and may alter each other’s structure as they interact:  Hundreds to thousands of degrees of freedom (DOF)
  • 18. Some techniques Surface representation, that efficiently represents the docking surface and identifies the regions of interest (cavities and protrusions)  Connolly surface  Clustered-Spheres  Alpha shapes Surface matching- that matches surfaces to optimize a binding score: (Fernandez et al.,2005)
  • 19. Surface Representation  Each atomic sphere is given the van der Waals radius of the atom  Rolling a Probe Sphere over the Van der Waals Surface leads to the Connolly surface (Fernandez et al.,2005)
  • 20. Clustered-Spheres Uses clustered-spheres to identify cavities on the receptor and protrusions on the ligand Regions where cavities (on the receptor) or protrusions (on the ligand) j i (Fernandez et al.,2005)
  • 21. Alpha Shapes In 2D an “edge” between two points is “alpha-exposed” if there exists a circle of radius alpha such that the two points lie on the surface of the circle and the circle contains no other points from the point set (Fernandez et al.,2005)
  • 22. Alpha Shapes: Example (Fernandez et al.,2005)
  • 23. 3-D Representation of a Protein Binding Site 6.7 4.2-4.7 5.2 4.8 5.1-7.1 (Fernandez et al.,2005)
  • 24. Surface Matching Find the transformation (rotation + translation) that will maximize the number of matching surface points from the receptor and the ligandFirst Condition  Find the best fit of the receptor and ligandUse energy calculations to refine the docking  Select the fit that has the minimum energy (Fernandez et al.,2005)
  • 25. CAPRI Critical Assessment of Prediction of Interactions launched to: To assess & compare current docking algorithms To stimulate further developments in the field (Gray et al.,2003)
  • 26. CAPRI Challenge (2002)T h e 7 C A P R I D o c k in g Ta rg e ts (Gray et al.,2003)
  • 27. DOCKDOCK works in 5 steps: Step 1 Start with crystal coordinates of target receptor Step 2 Generate molecular surface for receptor Step 3 Generate spheres to fill the active site of the receptor: The spheres become potential locations for ligand atoms Step 4 Matching: Sphere centers are then matched to the ligand atoms, to determine possible orientations for the ligand Step 5 Scoring: Find the top scoring orientation (Gray et al.,2003)
  • 28. Docking protocol (Gray et al.,2003)
  • 29. Docking protocolRANDOM START POSITION Creation of a decoy begins with a random orientation of each partner and a translation of one partner along the line of protein centers to create a glancing contact between the proteins (Gray et al.,2003)
  • 30. Docking protocolLOW-RESOLUTION MONTE CARLO SEARCH One partner is translated and rotated around the surface of the other The score is based in the correctness of each decoy and residue-residue interactions terms (Gray et al.,2003)
  • 31. Docking protocolHIGH-RESOLUTION REFINEMENT Side-chains are added to the protein backbones to changing the energy surface• A filter is employed to detect inferior decoys and reject them without further refinement (Gray et al.,2003)
  • 32. Docking protocolCLUSTERING & PREDICTIONS The search procedure is repeated to create approximately 105 decoys per target The 200 best-scoring decoys are then clustered The clusters with the most members are selected as the final predictions and ranked according to cluster sizes (Gray et al.,2003)
  • 33. Scoring Function To evaluate the interactions to discriminate the observed mode from others Binding affinity of the complex to be worked out Energetically favorable complexes to be predicted Large no: of degrees of freedom to be considered (Gray et al.,2003)
  • 34. PROTEIN-LIGAND DOCKING# A molecular modeling technique# Goal is to predict the position and orientation of a ligand when it is bound to a protein receptor or enzyme# Pertinent to field of drug design
  • 35. In drug designing… Drugs are small molecules of therapeutic importance Drug discovery costs are too high [~$800 millions] Time consuming [8~14 years] Drugs interact with their receptors in a highly specific and complementary manner. Effort  to cut down the research timeline and cost by reducing lab experiment  use computer modelling. (Wei et al ., 2004)
  • 36. contd… By computational means, screen large databases of potential drugs against protein targets HIV protease inhibitors - Invirase ,Norvir , Crixivan Influenza neuraminidase inhibitor - zanamivir (Wei et al ., 2004)
  • 37. DOCK: Example HIV-1 Protease Active Site (Aspartyl groups) (Wei et al ., 2004)
  • 38. TRADITIONAL DRUG DESIGN Natural ligand / Screening Biological Testing Drug Design Cycle If promisingSynthesis of New Compounds Pre-Clinical Studies (Wei et al ., 2004)
  • 39. SBDD drug targets (usually proteins)  binding of ligands to the target (docking) ↓ “rational” drug design (benefits = saved time and $$$) (Wei et al ., 2004)
  • 40. Structure-based Drug Design (SBDD) Natural ligand / Screening Molecular Biology & Protein Chemistry 3D Structure Determination of Target and Target-Ligand Complex Modelling Drug Design Cycle Structure Analysis Biological Testingand Compound Design If promising Synthesis of New Compounds Pre-Clinical Studies (Wei et al ., 2004)
  • 41. contd… Ligand Targetdatabase Protein Molecular docking Ligand docked into (Wei et al ., 2004) protein’s active site
  • 42. Molecular Docking Introduction Page
  • 43. Molecular Docking Page Introduction Page
  • 44.  Input Page
  • 45. Input Page (cont..)
  • 46. Submitting Job
  • 47. Results
  • 48. Results (in visualization form)
  • 49. Introduction The voltage-gated sodium channel underlies the propagation of action potentials in neuronal cells of both vertebrates and invertebrates. During an action potential of the sodium channel undergoes transitions between activated and inactivated functional states, and toxins binding to specific sites on the channel and the channel pore. (Andrias et al .,2006)
  • 50. Transmembrane topology of the voltage- gated sodium channel (Andrias et al .,2006)
  • 51. Model of voltage- gated sodium channel (Andrias et al .,2006)
  • 52. Chemical structure (Andrias et al .,2006)
  • 53. Fenvalerate (Andrias et al .,2006)
  • 54. Acrinathrin (Andrias et al .,2006)
  • 55. Docking ProgramsMore information in: http://www.bmm.icnet.uk/~smithgr/soft.htmlThe programmes are:  DOCK (I. D. Kuntz, UCSF)  AutoDOCK (Arthur Olson, The Scripps Research Institute)  RosettaDOCK (Baker, Washington Univ., Gray, Johns Hopkins Univ.) (Smith and Michael , 2002)
  • 56. PROTEIN-LIGAND DOCKING Affinity- (Accelrys Inc.) AutoDock- (The Scripps Research institute) FlexX -(BioSolve IT) GLIDE- (Schrödinger ) GOLD - (CCDC) LIGPLOT -(University College of London) FlexiDOCK -(Tripos) (Smith and Michael , 2002)
  • 57. Protein-Legand & Protein-Protein Docking DOCK -(UCSF Molecular Design Institute ) GRAMM- (SUNY) ICM-Dock- (MolSoft LIC) (Smith and Michael ,2002)
  • 58. CONCLUSION Protein docking is important in : Understanding / predicting interactions Developing drugs and cures The field continuous to progress & is developed by CAPRI
  • 59. Discussion
  • 60. Have a Nice Day !