Dewetting-Controlled Binding of Ligands to Hydrophobic Pockets

We report on a combined atomistic molecular dynamics simulation and implicit solvent analysis of a generic hydrophobic pocket-ligand (host-guest) system. The approaching ligand induces complex wetting-dewetting transitions in the weakly solvated pocket. The transitions lead to bimodal solvent fluctuations which govern magnitude and range of the pocket-ligand attraction. A recently developed implicit water model, based on the minimization of a geometric functional, captures the sensitive aqueous interface response to the concave-convex pocket-ligand configuration semiquantitatively.

Figure 1

(a) Sketch of the generic model. The pocket has a radius $R$. The methane (Me) ligand is fixed at a distance $d$ from the wall surface. (b) MD simulation snapshot illustrating the wall/ligand/water system.

Figure 2

MD simulation results for the free energy $G(N_w)$ vs pocket water occupancy $N_w$ in pocket $R8$ for ligand distances $d=0.0$, 2.5, 4.0, 5.5, 6.5, and 9 Å. The curves are shifted vertically and we use two scales (1 and 2 $k_{B}T$) for a better illustration. The right panel exemplifies the water density ($\rho$) distribution around pocket and ligand for selected $d$.

Figure 3

VISM solution of the aqueous interface for the $R8$ system. (a) and (b), full 3D interface for the ligand at $d=4.5$ for one surface (i) and two separated surfaces (ii) as initial boundary inputs, respectively. (c) and (d), the bisected interface for initially one surface (i) and two surfaces (ii), respectively, for distances $d=-2$, 2, 4.5, and 9 Å [black, magenta (light gray), blue (dark gray), and red (medium gray)].

Figure 4

VISM free energies for the 1s (squares), 2s-wet (circles), and 2s-dry (triangles) branches for $R8$ (top) and $R5$ (bottom) and the solvent-mediated pmf between the pocket and ligand from MD simulations (solid lines) and the ensemble average (EA) over the VISM branches (filled circles).