On the Role of Dewetting Transitions in Host–Guest Binding Free Energy Calculations

Abstract

We use thermodynamic integration (TI) and explicit solvent molecular dynamics (MD) simulation to estimate the absolute free energy of host–guest binding. In the unbound state, water molecules visit all of the internally accessible volume of the host, which is fully hydrated on all sides. Upon binding of an apolar guest, the toroidal host cavity is fully dehydrated; thus, during the intermediate λ stages along the integration, the hydration of the host fluctuates between hydrated and dehydrated states. Estimating free energies by TI can be especially challenging when there is a considerable difference in hydration between the two states of interest. We investigate these aspects using the popular TIP3P and TIP4P water models. TI free energy estimates through MD largely depend on water-related interactions, and water dynamics significantly affect the convergence of binding free energy calculations. Our results indicate that wetting/dewetting transitions play a major role in slowing the convergence of free energy estimation. We employ two alternative approaches—one analytical and the other empirically based on actual MD sampling—to correct for the standard state free energy. This correction is sizable (up to 4 kcal/mol), and the two approaches provide corrections that differ by about 1 kcal/mol. For the system considered here, the TIP4P water model combined with an analytical correction for the standard state free energy provides higher overall accuracy. This observation might be transferable to other systems in which water-related contributions dominate the binding process.

Selected applications of calixarene derivatives

“…The computational results indicate that the cavity dehydration is the strongest driving force behind host-guest complexation in water. 77 Therefore it has been established that the presence of electron withdrawing functional groups at wide rim of calixarenes may lead to their strong interactions with water molecules, either via dipole-dipole attraction or via OH- bonds.…”

The electrostatic response of water to neutral polar solutes: Implications for continuum solvent modeling

“…The present observations are also insensitive to the choice of water model, as similar results are obtained with the TIP3P 47 and TIP4P 47 models for receptors CB [7] and β-CD (Figure 1(a)). In order to test whether these nonlinearities might result from cooperative solvation among the various polar groups of these host molecules, or perhaps from the special properties of water molecules sequestered within their binding cavities, [61][62][63] we ran analogous calculations for formaldehyde and methanol, whose carbonyl and hydroxyl groups match the main polar groups of the CBs and CDs, respectively. The normalized solvation responses of formaldehyde and methanol agree with those of the corresponding receptor families (Figure 1(a)) and yield similar nonlinearity metrics, α = 0.86 and α = 0.75, respectively.…”

Stochastic level-set variational implicit-solvent approach to solute-solvent interfacial fluctuations

“…Induced by solvent fluctuations, dewetting transitions have remarkable impact on the binding kinetics of guests to the CB [7]. 57,59 Here we use our stochastic level-set VISM approach to investigate the dewetting transition of the hydrophobic cavity of CB [7].…”

“…Such a drying process, i.e., dewetting transition or capillary evaporation, has been found in experiment and computer simulations [24][25][26]28,30,[33][34][35][36][54][55][56] and is known to play a crucial role in many important biological processes, such as receptorligand binding. 3,32,[57][58][59] We apply our stochastic level-set method to study the dewetting transition in two hydrophobic systems: two parallel hydrophobic plates, and the synthetic host molecule cucurbit [7]uril (CB [7]). By using the deterministic level-set method developed in our previous works, 29,39,41,42,45,46 we are able to find multiple local minima with different initial guesses.…”