Docking (molecular)

In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using for example scoring functions.

The associations between biologically relevant molecules such as proteins, nucleic acids, carbohydrates, and lipids play a central role in signal transduction. Furthermore, the relative orientation of the two interacting partners may affect the type of signal produced (e.g., agonism vs antagonism). Therefore docking is useful for predicting both the strength and type of signal produced.

Docking is frequently used to predict the binding orientation of small molecule drug candidates to their protein targets in order to in turn predict the affinity and activity of the small molecule. Hence docking plays an important role in the rational design of drugs. Given the biological and pharmaceutical significance of molecular docking, considerable efforts have been directed towards improving the methods used to predict docking.

Problem Definition
Molecular docking can be thought of as a problem of “lock-and-key”, where one is interested in finding the correct relative orientation of the “key” which will open up the “lock” (where on the surface of the lock is the key hole, which direction to turn the key after it is inserted, etc.). Here, the protein can be thought of as the “lock” and the ligand can be thought of as a “key”. Molecular docking may be defined as an optimization problem, which would describe the “best-fit” orientation of a ligand that binds to a particular protein of interest. However since both the ligand and the protein are flexible, a “hand-in-glove” analogy is more appropriate than “lock-and-key”. During the course of the process, the ligand and the protein adjust their conformation to achieve an overall “best-fit” and this kind of conformational adjustments resulting in the overall binding is referred to as “induced-fit”.



The focus of molecular docking is to computationally stimulate the molecular recognition process. The aim of molecular docking is to achieve an optimized conformation for both the protein and ligand and relative orientation between protein and ligand such that the free energy of the overall system is minimized.

Approaches to Molecular docking
Two approaches are particularly popular within the molecular docking community. One approach uses a matching technique that describes the protein and the ligand as complementary surfaces. The second approach simulates the actual docking process in which the ligand-protein pairwise interaction energies are calculated. Both approaches have significant advantages as well as some limitations. These are outlined below.

Shape Complementarity Methods
Geometric matching/ shape compelementarity methods describe the protein and ligand as a set of features that make them dockable. These features may include molecular surface/ complementary surface descriptors. In this case, the receptor’s molecular surface is described in terms of its solvent-accessible surface area and the ligand’s molecular surface is described in terms of its matching surface description. The complementarity between the two surfaces amounts to the shape matching description that may help finding the complementary pose of docking the target and the ligand molecules. Another approach is to describe the hydrophobic features of the protein using turns in the main-chain atoms. Yet another approach is to use a Fourier shape descriptor technique described in [ref]. Whereas the shape complementarity based approaches are typically fast and robust, they cannot usually model the movements or dynamic changes in the ligand/ protein conformations accurately, although recent developments allow these methods to investigate ligand flexibility. Shape complementarity methods can quickly scan through several thousand ligands in a matter of seconds and actually figure out whether they can bind at the protein’s active site, and are usually scalable to even protein-protein interactions. They are also much more amenable to pharmacophore based approaches, since they use geometric descriptions of the ligands to find optimal binding.

Simulation Processes
The simulation of the docking process as such is a much more complicated process. In this approach, the protein and the ligand are separated by some physical distance, and the ligand finds its position into the protein’s active site after a certain number of “moves” in its conformational space. The moves incorporate rigid body transformations such as translations and rotations, as well as internal changes to the ligand’s structure including torsion angle rotations. Each of these moves in the conformation space of the ligand induces a total energetic cost of the system, and hence after every move the total energy of the system is calculated. The obvious advantage of the method is that it is more amenable to incorporating ligand flexibility into its modeling whereas shape complementarity techniques have to use some ingenious methods to incorporate flexibility in ligands. Another advantage is that the process is physically closer to what happens in reality, when the protein and ligand approach each other after molecular recognition. A clear disadvantage of this technique is that it takes longer time to evaluate the optimal pose of binding since they have to explore a rather large energy landscape. However grid-based techniques as well as fast optimization methods have significantly ameliorated these problems.

The Mechanics of Docking
To perform a docking screen, the first requirement is a structure of the protein of interest. Usually the structure has been determined using a biophysical technique such as x-ray crystallography, or less often, NMR spectroscopy. This protein structure and a database of potential ligands serve as inputs to a docking program. The success of a docking program depends on two components: the search algorithm and the scoring function.

The search algorithm
The search space consists of all possible orientations and conformations of the protein paired with the ligand. With present computing resources, it is impossible to exhaustively explore the search space—this would involve enumerating all possible distortions of each molecule (molecules are dynamic and exist in an ensemble of conformational states) and all possible rotational and translational orientations of the ligand relative to the protein at a given level of granularity. Most docking programs in use account for a flexible ligand, and several are attempting to model a flexible protein receptor. Each "snapshot" of the pair is referred to as a pose. There are many strategies for sampling the search space. Here are some examples:
 * 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
The scoring function takes a pose as input and returns a number indicating the likelihood that the pose represents a favorable binding interaction.

Most scoring functions are physics-based molecular mechanics force fields that estimate the energy of the pose; a low (negative) energy indicates a stable system and thus a likely binding interaction. An alternative approach is to derive a statistical potential for interactions from a large database of protein-ligand complexes, such as the Protein Data Bank, and evaluate the fit of the pose according to this inferred potential.

There are a lot of structures from X-ray diffraction for complexes between proteins and high affinity ligands, but very few for low affinity ligands as these do not stay bound for long enough to be seen. Scoring functions trained with this data can dock high affinity ligands correctly, but they will also give plausible docked conformations for ligands that really are inactive. This gives a large number of false positive hits, i.e., ligands predicted to bind to the protein that actually don't when placed together in a test tube.

One way to reduce the number of false positives is to recalculate the energy of the top-hit poses using a higher resolution (and therefore slow) technique like Generalized Born or Poisson-Boltzmann methods. However, typically the researcher will screen a database of tens to hundreds of thousands of compounds and test the top 60 or so in vitro, and to identify any true binders is still considered a success.

Applications
A binding interaction between a small molecule ligand and a enzyme protein may result in activation or inhibition of the enzyme. If the protein is a receptor, ligand binding may result in agonism or antagonism. Docking is most commonly used in the field of drug design — most drugs are small organic molecules, and docking may be applied to:
 * hit identification - docking combined with a scoring function can be used to quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest (see virtual screening).
 * lead optimization - docking can be used to predict in where and in which relative orientation a ligand binds to a protein (also referred to as the binding mode or pose). This information may in turn be used to design more potent and selective analogs.