Proteomics/Protein - Protein Interactions/Types of Interactions

Page Edited and Updated by: Christopher Fucile E-mail: cff8255@rit.edu

This Section:

Molecular Docking
Molecular docking is the technique that is used to study molecular binding and   how   molecules  bind. The term “docking” is mostly related to protein molecule interactions. There are several types of molecular docking for protein interactions: Of all these Protein ligand interaction techniques are the most widely used techniques.
 * If a protein interacts with a ligand : protein-ligand interaction
 * If a protein interacts with another protein: protein-protein interaction
 * If a protein binds to DNA: protein-DNA interactions

Advantages: One of the major advantages conferred by docking is that it allows researchers to quickly screen large databases of potential drugs which would otherwise require tedious and prolonged work in the lab using traditional drug discovery procedures.

The Principle Behind Docking
The foremost thing that we need to start with a docking search is the sequence of our protein of interest. We then search for ligand sequences from suitable databases. These two components are the input for the docking method. There are two basic components of molecular docking:
 * The search algorithm
 * The scoring function

The Search Algorithm
A search algorithm finds the best docking pose measured by the scoring function. Since it is impossible to do an exhaustive search most of the docking tools resort to the most flexible ligands available. There are several ways for sampling the search space.

Some examples are:
 * Use a coarse-grained molecular dynamics simulation to propose energetically reasonable poses
 * Use a "linear combination" of multiple structures determined for the same protein to emulate receptor flexibility
 * Use a genetic algorithm to "evolve" new poses that are successively more and more likely to represent favorable binding interactions.

The Scoring Function


A scoring function discriminates correct (experimentally verified) docking poses from incorrect ones. It estimates the binding affinity between ligand and receptor. To check whether the resultant pose is stable or not, we use several physics theories, such as Gibb's free energy. A low Gibb’s free energy confirms a stable conformation rather than a high energy which denotes an unstable complex. Another approach of the scoring function is to establish a conformational relationship (based on statistical analysis) from large protein databases and then evaluate the stability and fitness of the pose. One of the main problems with utilizing a database technique for the docking function is the increased rate of false positives.

Protein-Protein Docking Interactions
Protein-protein interactions occur between two proteins that are similar in size. The interface between the two molecules tend to be flatter and smoother than those in protein-ligand interactions. Protein-protein interactions are usually more rigid; the interfaces of these interactions do not have the ability to alter their conformation in order to improve binding and ease movement. Conformational changes are limited by steric constraints and thus are said to be rigid.

Protein Receptor-Ligand Docking
Also known as the molecular docking technique, protein receptor -ligand 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 is both high specificity and induced fit within these interfaces with specificity increasing with rigidity. Protein receptor-ligand can either have a rigid ligand and a flexible receptor, or a flexible ligand with a rigid receptor.

Rigid Ligand with a Flexible Receptor
The native structure of the rigid ligand flexible receptor often maximizes the interface area between the molecules. They move within respect to one another in a perpendicular direction in respect to the interface. This allows for binding of a receptor with a larger than usual ligand. Normally when there is ligand overlap in the docking interface, energy penalties incur. If the van der Waals forces can be decreased,  energy loss in the system will be minimized. This can be accomplished by allowing flexibility in the receptor. Flexible receptors allow for docking of a larger ligand than would be allowed for with a rigid receptor....

Flexible Ligand with a Rigid Receptor
When the fit between the ligand and receptor does not need to be induced, the receptor can retain its rigidity while maintaining the free energy of the system. For successful docking, the parameters of the ligand need to be constant and the ligand must be slightly smaller in size than that of the receptor interface. No docking is completely rigid though; there is intrinsic movement which allows for small conformational adaptation for ligand binding. When the six degrees of freedom for protein movement are taken into consideration (three rotational, three translational), the amount of inherent flexibility allowed by the receptor is even greater. This further offsets any energy penalty between the receptor and ligand, allowing for easier, more energetically favorable binding between the two.

Docking Problems
The search space consists of all possible conformations and configurations. With present computing resources, it would be impossible to exhaustively explore the search space for all possible poses (a pose is the name given to the configuration of the conformation of a molecule in a coordinate system). Needless to say, every docking simulation is a trade-off between accuracy and speed and a good docking tool is expected to maintain a reasonably good balance between the two. See also Protein-Protein Interaction Network Visualization and  Prediction Methods for Interactions and Docking.

References(Open Access)
1. "Docking (molecular)." Wikipedia, The Free Encyclopedia.. Wikimedia Foundation, Inc. 9 Apr 2007 ..