Macromolecular Docking - Background

Background

The biological roles of most proteins, as characterized by which other macromolecules they interact with, are known at best incompletely. Even those proteins that participate in a well-studied biological process (e.g., the Krebs cycle) may have unexpected interaction partners or functions which are unrelated to that process.

In cases of known protein–protein interactions, other questions arise. Genetic diseases (e.g., cystic fibrosis) are known to be caused by misfolded or mutated proteins, and there is a desire to understand what, if any, anomalous protein–protein interactions a given mutation can cause. In the distant future, proteins may be designed to perform biological functions, and a determination of the potential interactions of such proteins will be essential.

For any given set of proteins, the following questions may be of interest, from the point of view of technology or natural history:

• Do these proteins bind in vivo?

If they do bind,

• What is the spatial configuration which they adopt in their bound state?
• How strong or weak is their interaction?

If they do not bind,

• Can they be made to bind by inducing a mutation?

Protein–protein docking is ultimately envisaged to address all these issues. Furthermore, since docking methods can be based on purely physical principles, even proteins of unknown function (or which have been studied relatively little) may be docked. The only prerequisite is that their molecular structure has been either determined experimentally, or can be estimated by a protein structure prediction technique.

Protein–nucleic acid interactions feature prominently in the living cell. Transcription factors, which regulate gene expression, and polymerases, which catalyse replication, are composed of proteins, and the genetic material they interact with is composed of nucleic acids. Modeling protein–nucleic acid complexes presents some unique challenges, as described below.