Molecular Simulations of Thermodynamic Properties for the Systemα‐Cyclodextrin/Alcohol in Aqueous Solution

Abstract

Free-energy calculations based on molecular simulations provide access to a wide range of thermodynamic properties such as the solubility and partitioning of a molecule in and between various phases. It is demonstrated how molecular dynamics free-energy simulations may be used to obtain the solubilities of primary alcohols and n-alkanes in water and binding affinities of primary alcohols to a-cyclodextrin. The equivalence of two distinct routes to calculate binding free energies is shown leading to the conclusion that host-guest binding affinities may be used to probe the underlying molecular force field.

Insights into Noncovalent Binding Obtained from Molecular Dynamics Simulations

“…The results of the 10‐µs MD simulation for 1‐butanol binding carried out in the present work and the binding free enthalpies computed in previous studies , are summarized in Tabs. and .…”

“…are reported for two different force fields , and are calculated from Eqs. and of this work, respectively, or are taken from previous studies employing the double decoupling (DD) or potential of mean force (PMF) route, respectively , .…”

“…Note that in the evaluation of Eq. of our previous work the integration over the bound region was erroneously performed from the minimum to the flat part of the PMF instead of spanning the entire range between the two flat regions. As consequence, the value reported here is more negative by 1.7 kJ mol −1 than the one shown in Fig.…”

“…A plethora of methods to calculate free‐energy changes along these paths have been developed and extensively reviewed . In previous studies , , umbrella sampling simulations were employed for the physical path and a combination of thermodynamic integration and enveloping distribution sampling for the alchemical path and their equivalency for binding of primary alcohols to α ‐cyclodextrin was shown. For the present work, this analysis was extended by direct counting to obtain the standard binding free enthalpy according to …”

Lessons Learned from the Calculation of One-Dimensional Potentials of Mean Force [Article v1.0]

“…The latter class of methods requires an integration of the PMF over a bound and unbound region, corresponding to the reversible work to transfer the ligand (or guest molecule) from the bulk to the binding pose inside the host. In principle, the PMF-derived estimate of the binding free enthalpy can be validated by results from double decoupling [16,17] or, when possible, by direct counting estimation, based on long unbiased simulations [18,19]. PMF calculations for a specific binding process, are based upon either equilibrium methods such as umbrella sampling [20,21], local elevation [22] or metadynamics [23], adaptive biasing force [24], forward flux sampling [25] or on non-equilibrium methods such as steered MD [26].…”