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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 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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Rajendra Kumar
Protein Docking
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
Proteins Are…
To place a ligand into the binding site of a protein in the appropriate manner for optimal interactions with a receptor protein
Goal: To be able to search a database of molecular structures and
retrieve all molecules that can interact with the query structure
Definition
Aim: predict the structure of a protein complex from its partners
+
Monomers
Complex
Protein-protein Docking
(James meiler,2007)
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
Types of Docking studies
Rigid Body Docking: No modification in bond angles, lengths & torsion
angles of the components
Flexible Docking : Takes in to the conformational changes
Rigid Vs Flexible docking
Protein docking is the computational determination of protein complex structure from individual protein structures.
(Smith and Sternberg, 2002)
Ligand binds to the active site of protein
Binding leads to conformational changes in protein
Conformational changes thermodynamically most stable
Lowest Gibb’s energy
Interactions lead to …
Protein –Protein interaction Thermodynamics
(Smith and Sternberg, 2002)
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.
Why docking is important?
Structure of protein of interest should be known
X-ray Crystallography NMR Spectroscopy
Basic Requirements For Docking
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).
X-Ray Diffraction
( Hubbard, 2006)
cont..
( Hubbard, 2006)
( Hubbard, 2006)
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)
Nuclear Magnetic Resonance
(James, 1998)
Both molecules are flexible and may alter each other’s structure as they interact:
Hundreds to thousands of degrees of freedom (DOF)
Why this is difficult?
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:
Some techniques
(Fernandez et al.,2005)
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
Surface Representation
(Fernandez et al.,2005)
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)
i
j
Clustered-Spheres
(Fernandez et al.,2005)
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
Alpha Shapes
(Fernandez et al.,2005)
Alpha Shapes: Example
(Fernandez et al.,2005)
5.24.2-4.7
6.7
4.8
5.1-7.1
3-D Representation of a Protein Binding Site
(Fernandez et al.,2005)
Find the transformation (rotation + translation) that will maximize the number of matching surface points from the receptor and the ligand
First Condition Find the best fit of the receptor and ligand
Use energy calculations to refine the docking Select the fit that has the minimum energy
Surface Matching
(Fernandez et al.,2005)
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)
CAPRI
The 7 CAPRI Docking Targets
CAPRI Challenge (2002)
(Gray et al.,2003)
DOCK works in 5 steps:
Step 1 Start with crystal coordinates of target receptor
Step 2 Generate molecular surface for receptor
Step 3Step 3 Generate spheres to fill the active site of the receptor: Generate spheres to fill the active site of the receptor: The spheres become potential locations for ligand atomsThe 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
DOCK
(Gray et al.,2003)
Docking protocol
(Gray et al.,2003)
RANDOM START POSITIONRANDOM 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
Docking protocol
(Gray et al.,2003)
LOW-RESOLUTION MONTE CARLO SEARCHLOW-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
Docking protocol
(Gray et al.,2003)
HIGH-RESOLUTION REFINEMENTHIGH-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
Docking protocol
(Gray et al.,2003)
CLUSTERING & 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
Docking protocol
(Gray et al.,2003)
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
Scoring Function
(Gray et al.,2003)
# 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
PROTEIN-LIGAND DOCKING
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.
In drug designing…
(Wei et al ., 2004)
By computational means, screen large databases of potential drugs against protein targets
HIV protease inhibitors - Invirase ,Norvir , Crixivan
Influenza neuraminidase inhibitor - zanamivir
contd…
(Wei et al ., 2004)
Active Site(Aspartyl groups)
DOCK: Example HIV-1 Protease
(Wei et al ., 2004)
TRADITIONAL DRUG DESIGN
Natural ligand / Screening
Biological Testing
Synthesis of New Compounds
Drug Design CycleDrug Design Cycle
If promising
Pre-Clinical Studies
(Wei et al ., 2004)
drug targets (usually proteins) binding of ligands to the target (docking)
↓
“rational” drug design
(benefits = saved time and $$$)
SBDD
(Wei et al ., 2004)
Molecular Biology & Protein Chemistry
3D Structure Determination of Target and Target-Ligand Complex
Modelling
Structure Analysisand Compound Design
Biological Testing
Synthesis of New Compounds
If promising
Pre-Clinical Studies
Drug Design CycleDrug Design Cycle
Natural ligand / Screening
Structure-based Drug Design (SBDD)
(Wei et al ., 2004)
Ligand database
Target Protein
Molecular docking
Ligand docked into protein’s active site
contd…
(Wei et al ., 2004)
Molecular Docking Introduction Page
Introduction Page
Molecular Docking Page
Input Page
Input Page (cont..)
Submitting Job
Results
Results (in visualization form)
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.
Introduction
(Andrias et al .,2006)
Transmembrane topology of the voltage- gated sodium channel
(Andrias et al .,2006)
Model of voltage- gated sodium channel
(Andrias et al .,2006)
Chemical structure
(Andrias et al .,2006)
Fenvalerate
(Andrias et al .,2006)
Acrinathrin
(Andrias et al .,2006)
More information in: http://www.bmm.icnet.uk/~smithgr/soft.html
The programmes are:
DOCK (I. D. Kuntz, UCSF)
AutoDOCK (Arthur Olson, The Scripps Research Institute)
RosettaDOCK (Baker, Washington Univ., Gray, Johns Hopkins Univ.)
Docking Programs
(Smith and Michael , 2002)
Affinity- (Accelrys Inc.) AutoDock- (The Scripps Research institute) FlexX -(BioSolve IT) GLIDE- (Schrödinger ) GOLD - (CCDC) LIGPLOT -(University College of London) FlexiDOCK -(Tripos)
PROTEIN-LIGAND DOCKING
(Smith and Michael , 2002)
DOCK -(UCSF Molecular Design Institute )
GRAMM- (SUNY)
ICM-Dock- (MolSoft LIC)
Protein-Legand & Protein-Protein Docking
(Smith and Michael ,2002)
Protein docking is important in :
Understanding / predicting interactions
Developing drugs and cures
The field continuous to progress & is developed by CAPRI
CONCLUSION
Discussion
Have a Nice Day !
![Docking interactions in protein kinase and phosphatase ...interacting protein–protein motifs for MAP kinases and tyrosine phosphatases [12,13]. Docking interactions in protein phosphatases](https://img.dokumen.tips/doc/110x75/60ee63efe2bdd8639d7712a5/docking-interactions-in-protein-kinase-and-phosphatase-interacting-proteinaprotein.jpg)
