Accommodating protein flexibility for structure based drug design

27 Apr

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.

Recently, standard FEP and TI protocols have been extended to efficiently incorporate conformational changes associated with ligand binding () developed an independent-trajectory thermodynamics-integration (IT-TI) method that computes absolute and relative binding free energies using multiple independent trajectories to improve configurational sampling.

In their study on peramivir binding to H5N1 avian influenza virus neuraminidase, IT-TI was utilized to extensively sample the phase space accessible to the flexible loop regions that interact with the ligand.

Finally, different approaches that incorporate protein dynamics, e.g.

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

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.

accommodating protein flexibility for structure based drug design-72

Several computational studies will be presented that discuss the validity and possible limitations of such approaches.configurational entropy, the modeling of solvation effects, and the precise quantification of the free energy associated with the protein's conformational change coupled to ligand binding.) the two mechanisms can be characterized as either a path from the ligand-unoccupied open (UO) state to the ligand-bound closed (BC) state either via the ligand-unoccupied closed (UC) state (in case of conformational-selection mechanism; red path in Scheme representing the two mechanisms of protein conformational change coupled to ligand binding.In the conformational-selection mechanism (red line) the apo form of the protein (unoccupied-open, UO) adapts to a certain probability a closed conformation where two basins of the Hamiltonian describe the open and closed protein state.Additional computational studies will be presented that discuss the validity of the different methods that incorporate protein flexibility during docking.Furthermore, three additional important issues will be discussed that need further consideration in the development of future flexible docking methods: The modeling of protein dynamics, i.e.