MOLECULAR

DOCKING
TOPICS TO BE COVERED
● What is Docking ?
● Aim of Docking
● Types of Docking (on the basis of ligand)
● Kinds of Docking
● Scoring Functions
● Searching Algorithms
● High throughput Screening
● Virtual Screening and Docking
● Conclusion

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•
WHAT IS DOCKING
Molecular docking is the study of how two or more molecular structures (e.g. drug
and enzyme or protein) fit together.
• In a simple definition, docking is a molecular modeling technique that is used to
predict how a protein (enzyme) interacts with small molecules (ligands).
• . The ability of a protein (enzyme) and nucleic acid to interact with small molecules
to form a supramolecular complex plays a major role in the dynamics of the
protein, which may enhance or inhibit its biological function.
• The behavior of small molecules in the binding pockets of target proteins can be
described by molecular docking.

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 AIM OF
DOCKING
• Molecular docking or computer-simulated ligand binding is a powerful technique
for investigating intermolecular interactions.
• To characterize the relative goodness-of-fit of the peptide. This is to identify the
most probable position and orientation of a peptide within the MHC binding
groove.
• The basis of docking is to identify the most probable complementation in size,
shape, and intermolecular forces of a given MHC-peptide pair.
• A complication for MHC class II molecules is the open nature of the binding
groove i.e the peptide can hang from the ends thus it can be extended in shape
when bound to MHC.
• A single peptide may have multiple binding registers (i.e. core residues) that
interact with a given receptor. In such cases, the binding modes of all possible core
residues should be analyzed.

[Link]
molecular
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The following figure shows how a ligand interacts with
protein through molecular docking.

Receptor

Complex ( ligand docked into the active site) 4

Based on the types of ligand, docking can be

Protein Nucleic Acid docking

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Protein Ligand Docking
• Protein–small molecule (ligand) docking represents a simpler end of the
complexity spectrum, and is useful in predicting molecules that may
potentially inhibit proteins.
• It aims to find the most favorable binding mode of a ligand in the protein
binding site usually by sampling a huge amount of conformations and
orientations.
• The feasible poses are scored with a physics-based, a partially experimental-
partially physics based or a completely experimentally fitted scoring
function to estimate the binding free energy.
• The two main objectives of this type of docking are to find a reliable binding
mode of a ligand and to separate ligands with favorable binding free energy
(actives) and sub-optimal interactions (inactive).

[Link]
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Protein Ligand Docking

Back Next
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Protein-Nucleic Acid Docking
● The interactions between protein and nucleic acids play essential roles in various essential
biological processes, including DNA replication, RNA transcription, RNA splicing,
degradation of nucleic acids and protein synthesis.
● New structures of protein–nucleic acid complexes are solved and the structural details of the
interactions are analyzed.
● In silico docking of proteins with nucleic acids, by building theoretical models of the complex
structures at atomic details, can yield sufficient information to build a working hypothesis
and guide further experimental analyses to identify important amino acids or nucleotide
residues.
● First, a rigid body global search is performed and geometrically plausible protein–nucleic
acid complex structures are generated. In this process, user-defined restraints can be applied
to limit the search space.
● The resulting models are scored and ranked using statistical potentials, developed specifically
for protein–RNA or protein–DNA complexes. The best-scored structures are then clustered
and representatives of the largest clusters are selected for structural optimization by energy
minimization before being presented to the customer.
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[Link]
Protein- Nucleic Acid Docking

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Protein-Protein Docking
● Protein–protein docking is typically much more complex.
● The reason is that proteins are flexible and their conformational space is quite vast.
● Protein-protein docking is the computational prediction of protein complex structure given
the individually solved component protein structure.
● It is an important means for understanding the physicochemical forces that underlie
macromolecular interactions and a valuable tool for modeling protein complex structures.

[Link]
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 KINDS OF DOCKING
RIGID DOCKING
• If the bond angles, bond lengths and torsion angles of the components are not modified at any stage of
complex generation,is known as rigid body docking.
• The objects cannot change their spatial shape during the docking process.

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Flexible Docking
● Flexible docking is when some residues in the interacting bodies (receptor and ligand) are kept
flexible leaving the rest of the part rigid.
● Model changes in internal geometry of the interacting partners that may occur when a complex is
formed.

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COMPARISON BETWEEN RIGID AND
FLEXIBLE DOCKING

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BOUND DOCKING
In bound docking the goal is to reproduce a known complex. where the starting coordinates of the
individual molecules are. taken from the crystal of the complex.
The complex structure is known. The receptor and the ligand are pulled apart and then reassembled.

UNBOUND DOCKING
In unbound docking which is significantly more difficult problem, the starting coordiantes are taken
form unbound molecules.
Individually determined protein structures are used.

LOCAL DOCKING
In local docking, we assume that we have some information about the binding pockets of the two
proteins.

GLOBAL DOCKING
It is done if absolutely no information is available about the binding sites in the protein.
Global docking assumes a spherical general structure of the proteins and rotates the smaller protein
(ligand) around the larger protein (receptor).
It also randomizes the starting position of the unbound proteins in every run, so their position in the
input structure does not matter as much.
[Link]
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CONCLUSION
● Molecular docking is a computational procedure that aims to predict the favored orientation of a ligand to its
macromolecular target (receptor), when these are bound to each other to form a stable complex.275 Although
each docking program operates slightly differently, they share common features that involve ligand and
receptor, sampling, and scoring.

● Sampling entails conformational and orientational location of the ligand within the constraints of the receptor-
site binding. A scoring function selects the best ligand conformation, orientation, and translation (referred
to as poses), and classifies ligands in rank order.

● A successful docking exercise must accurately predict either or both ligand structure (pose prediction) and its
binding propensity (affinity prediction). Available docking programs differ essentially in ligand placement in
the
“combining” site, exploration of conformational space, and scoring or binding estimate.

● The interaction with the ligand relies both on the protein backbone fold in the region of the binding site and on
the orientation of the side chains in that binding site.

● One of the most significant limitations in docking is that it is typically performed while keeping the protein
surface rigid, which prevents consideration of the effects of induced-fit within the binding site.
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THANK YOU