Accommodating protein flexibility for structure based drug design

IT-TI was designed for use with distributed computing and consequently allows a significantly more rapid computation of absolute free energies of binding compared to standard TI or FEP calculations for a series of ligands.An alternative method designed to predict in the configuration and binding affinity of a ligand to a specific receptor is receptor-ligand docking.As the ligand binds to the protein, the water molecules in the shell surrounding the hydrophobic moieties of the ligand and the binding site of the protein are released into the bulk solvent and gain translational, rotational, and vibrational entropy thereby lowering the free energy of the protein-ligand complex.However, recent studies () found that disordered water molecules with density smaller than bulk density bind to small but solvent-accessible hydrophobic cavities.The trend between ligand-protein interaction strength and mechanism of conformational change is intuitive and can be interpreted utilizing the free-energy landscape model ( are required to induce and stabilize the holo conformation and drive the overall free energy of the protein-ligand complex to a more negative value than the unbound apo conformation.If the energy difference between the apo and the holo protein form is small (, bottom panel), the holo conformation is frequently visited by the unbound protein and the ligand can bind to this protein conformation.


configurational entropy, and solvation effects into docking will be highlighted.

For example, X-ray crystallography and kinetic measurements on ligand binding to the antibody SPE7 showed that ligands bind to pre-existing conformations of SPE7 followed by induced fit generating the final high-affinity protein-ligand complex (Over the past few decades, many computational concepts have emerged that incorporate different levels of protein flexibility into the modeling of protein-ligand association.

Many methods are applied to study individual protein-ligand complexes, such as molecular-dynamics (MD) or Monte-Carlo (MC) simulations.

Molecular recognition between receptors and ligands plays a fundamental role in virtually all biochemical processes in living organisms.

In many instances, ligands such as hormones or neurotransmitters are located outside the cell and non-covalently bind to receptors, e.g. This association process results in conformational changes that lead to subsequent signaling events inside the cell.Additional computational studies will be presented that discuss the validity of the different methods that incorporate protein flexibility during docking.


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