Chemistry Reference
In-Depth Information
INDUCED FIT
Different mechanisms can play a role in the variety of conformational changes
occurring upon protein-ligand binding. The term induced fit is used to describe
the resultant tight structural complementarity of the interaction partners taken into
consideration by docking methods. Handling the protein as flexible is not
common and still remains a challenge in contrast to ligand flexibility in docking
protocols. This is particularly true, if we consider computational difficulties/time
involved [270-319].
Important for protein function and ligand binding is protein flexibility. At finite
temperatures, this can result in numerous motions including rotations about single
bonds up to large-scale collective movements of loops, secondary structure
elements or even entire domains. Binding can depend on motion in certain parts of
the protein, affect flexibility of the protein (altering its dynamics properties),
modulating the possibilities of motion and compensate as well for unfavorable
entropic contributions from molecular interactions.
The ability of binding partners to have conformational adaption to each other,
i.e.
plasticity, is important for docking whereas ligands can adopt a conformation
suitable for tight interaction with their target protein that often does not
correspond to the lowest energy conformation of the ligand. Proteins can also
have a variety of changes on binding from small side chain adaptations to large
domain movements.
The concept of induced fit is often used to describe any conformational change in
a protein due to ligand binding whereas the well-known lock-and-key principle
should remain valid (mutual adaptation).
The model of conformational selection challenges induced fit whereas the protein
conformational ensemble is re-distributed upon binding giving preference to
population of states resulting in a net gain in free energy. However, even if
conformational selection is the actual mechanism, the ligand induces the
observable conformational changes.
