The pKa and, therefore, the protonation state of a titratable group depend on the solution pH and electrostatic environment of the titratable group. Receptor-ligand complex formation can change the electrostatic environment of both the receptor and ligand, potentially inducing a shift in pKa of groups on either partner and rendering the free energy of complex formation pH-dependent. Conventionally, binding free energy calculations typically do not account for pH effects and employ the fixed protonation states for titratable groups. In this work, we aim to demonstrate how proton (un)binding influences free energies of binding of a series of guest molecules to a synthetic host, cucurbit[7]uril (CB[7]). The pH-dependent free energy will be a sum of the free energy of binding neglecting the pH dependence (i.e. reference state) and a correction term where the pKa shifts upon binding are taken into account, the latter being calculated by performing constant pH molecular dynamics simulations. By employing thermodynamic integration to get the reference free energy of binding, we remove the dependence on the availability of experimental association constants and enable full prediction of the pH-dependent free energy profile. Our results show the large pKa shifts and change of free energies upon binding of the guests to the CB[7] host and agree well with the experimental data. Noticeably, the free energy of binding can change in the host-guest system by about 3~6 kcal/mol in the physiological pH levels. When employed to protein-ligand bindings, our method can predict significant pH-dependent changes in binding free energy and this will be critical for weak bases, which may act as drugs. Therefore, our work highlights the importance of accurately addressing the complex formation that accompanies proton (un)binding and the change in binding free energy upon such event and further suggests its high utility in computer-aided drug discovery.

Calculation of pH-dependent free energy of binding of host-guest complexes

248th National Meeting (2014)

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