Computation of the contribution from the cavity effect to protein-ligand binding free energy.

We present results of the investigation of the cavity creation/annihilation effect in view of formation of the protein-ligand (PL) complexes. The protein and ligand were considered as rigid structures. The change of the cavity creation/annihilation free energy DeltaG(cav) was calculated for three PL complexes using the thermodynamic integration procedure with the original algorithm for growing the interaction potential between the cavity and the water molecules. The thermodynamic cycle consists of two stages, annihilation of the cavity of the ligand for the unbound state and its creation at the active site of the protein (bound state). It was revealed that for all complexes under investigation, the values of DeltaG(cav) are negative and favorable for binding. The main contribution to DeltaG(cav) appears due to the annihilation of the cavity of the ligand. All computations were made using the parallel version of CAVE code, elaborated in our preceding work.

Cavitation free energy for organic molecules having various sizes and shapes.

Cavitation free energy DeltaG(cav), corresponding to the formation of an excluded volume cavity in water, is calculated for a large set of organic molecules employing the thermodynamic integration procedure, which is realized as the original two-step algorithm for growing the interaction potential between the hard cavity wall and the water molecules. A large variety of solute systems is considered. Their characteristic radii change in the range 3-7 A; spherical cavities with radii 3-6 A are also studied. The interaction between water molecules is described by the four-site nonpolarizable TIP4P model. The diversity of the trial molecular set is provided by using a specially formulated nonspherical criterion classifying the cavity shapes according to their deviation from a sphere. Molecular objects were partly taken from the data base NCI Diversity with the aid of this criterion. The so-computed free energies are approximated by the linear volume dependence DeltaG(cav)V = XiV, where V is the cavity volume. This relation works fairly well until the cavity size becomes very large (the effective radius larger than 7 A). The volume dependence valid for solutes of arbitrary shapes can be included in a calculation of the nonpolar free energy component as required in the implicit water model.