Bridging Calorimetry and Simulation through Precise Calculations of Cucurbituril–Guest Binding Enthalpies

Abstract

We used microsecond time scale molecular dynamics simulations to compute, at high precision, binding enthalpies for cucurbit[7]uril (CB7) with eight guests in aqueous solution. The results correlate well with experimental data from previously published isothermal titration calorimetry studies, and decomposition of the computed binding enthalpies by interaction type provides plausible mechanistic insights. Thus, dispersion interactions appear to play a key role in stabilizing these complexes, due at least in part to the fact that their packing density is greater than that of water. On the other hand, strongly favorable Coulombic interactions between the host and guests are compensated by unfavorable solvent contributions, leaving relatively modest electrostatic contributions to the binding enthalpies. The better steric fit of the aliphatic guests into the circular host appears to explain why their binding enthalpies tend to be more favorable than those of the more planar aromatic guests. The present calculations also bear on the validity of the simulation force field. Somewhat unexpectedly, the TIP3P water yields better agreement with experiment than the TIP4P-Ew water model, although the latter is known to replicate the properties of pure water more accurately. More broadly, the present results demonstrate the potential for computational calorimetry to provide atomistic explanations for thermodynamic observations.

Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition

“…50 For each run, the system was first solvated with exactly 1737 TIP3P water molecules (about 12 Å away from the solute) and then optimized to eliminate possible clashes. The water molecules were then equilibrated at 298 K for 1 ns, followed by an equilibration of the entire system from 200 to 298 K for 150 ps.…”

Evaluation and Minimization of Uncertainty in ITC Binding Measurements: Heat Error, Concentration Error, Saturation, and Stoichiometry

“…For example, modes of drug-receptor binding can sometimes be assigned based on knowledge of both ΔG and ΔH 14,15 . Moreover, the determination of ΔH, in addition to ΔG, expands the dataset available to test and improve the accuracy of molecular simulations: much as heats of vaporization and sublimation played a central role in defining the force field parameters used for liquid-state simulations 16–19 , so binding enthalpy data, particularly for experimentally and computationally tractable host-guest systems, should be useful to test and improve the force fields used for simulations of noncovalent binding 20,21 . For all of these applications, it is desirable to use procedures that minimize the uncertainty in the thermodynamic results and to have a quantitative understanding of these uncertainties.…”

Studying the role of cooperative hydration in stabilizing folded protein states

“…The resulting water globules were then cut to orthorhombic unit cells with side lengths of 42.0 Å × 42.0 Å × 147.0 Å for the extended state and 64.0 Å × 64.0Å × 64.0 Å for the other states. For each system treatment, the number of water molecules was adjusted to be equal for each of the states (Fenley et al, 2014). To standardize the geometries of the water molecules, every hydrogen atom was deleted and all the necessary hydrogen atoms and lone pairs were built using the appropriate geometry for the TIP3P and TIP4P-2005 models (oxygen-hydrogen bond lengths of 0.9572 Å, oxygen-lone pair bond lengths of 0.1546 Å, hydrogen-oxygen-lone pair bond angles of 52.26°, and hydrogen-oxygen-hydrogen bond angles of 104.52°).…”

“…Keeping the number of particles of each type constant, the difference in energy between a given state and the native state is simple to compute from the simulation (Fenley et al, 2014, Roy et al, 2014). $\mathrm{\Delta }{E}_{\mathit{native}}=E_{\mathit{state}}-E_{\mathit{native}}$…”

“…Whilst analyses of polar and non-polar contributions to the energy and free energy of protein folding have been performed previously (Lazaridis et al, 1995, Makhatadze and Privalov, 1993, Privalov and Makhatadze, 1993, Robertson and Murphy, 1997), to our knowledge this is the first study that considers the difference between direct and water-mediated hydrogen-bonding interactions. We address this by considering the three mechanisms described above using average energies from long-timescale molecular dynamics (MD) simulations (Fenley et al, 2014, Roy et al, 2014). As a test case, we consider the villin headpiece, one of the mainstays of protein-folding studies (Duan et al, 1998, Fernández et al, 2003, Freddolino and Schulten, 2009, Jayachandran et al, 2006, Kubelka et al, 2003, Lee et al, 2000, McKnight et al, 1996, Mittal and Best, 2010, Wang et al, 2003).…”