Binding of Organic Cations to a Cyclophane Host As Studied with Molecular Dynamics Simulations and Free Energy Calculations
- 1 May 1999
- journal article
- research article
- Published by American Chemical Society (ACS) in The Journal of Physical Chemistry B
- Vol. 103 (21), 4474-4480
- https://doi.org/10.1021/jp983513p
Abstract
We have studied the binding of two organic cations, an iminium (IM) and a guanidinium (GU), to a cyclophane host P4--4Na+, using molecular dynamics simulations and free energy calculations. A proper treatment of the long-range electrostatic forces is essential for the stability of these highly charged complexes, and a simple cutoff at 12 Å results in an artifactual dissociation of the IM−P4--4Na+ complex. Since the host is highly aromatic and the guests cationic, cation−π interactions play an important role in the complex stability. In free energy calculations, using a simple additive force field, we calculate that the relative free energy of association of IM and GU binding to the host is 2.3 kcal/mol favoring IM, which is of the correct sign but 1.4 kcal/mol too small in magnitude. Differences in van der Waals interaction energies are mainly responsible for the different binding strengths, and the host adopts different shapes when accommodating IM compared to GU. To approximately estimate the contribution to the complex stability from the polarization energy, we calculated the in vacuo interaction energies in the two complexes, using a nonadditive force field, previously shown to accurately describe alkali cation−aromatic interaction energies in vacuo. Adding the contribution from the polarization energy upon forming the two complexes in this calculation to the estimate from the free energy calculation, we obtain an improved relative binding free energy (−4.0 kcal/mol), which is in close agreement with the experimental value of −3.7 kcal/mol.Keywords
This publication has 12 references indexed in Scilit:
- Cation-π Interactions in Chemistry and Biology: A New View of Benzene, Phe, Tyr, and TrpScience, 1996
- A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic MoleculesJournal of the American Chemical Society, 1995
- Molecular Dynamics Simulations on Solvated Biomolecular Systems: The Particle Mesh Ewald Method Leads to Stable Trajectories of DNA, RNA, and ProteinsJournal of the American Chemical Society, 1995
- Molecular recognition in aqueous media. New binding studies provide further insights into the cation-.pi. interaction and related phenomenaJournal of the American Chemical Society, 1993
- Free energy calculations: Applications to chemical and biochemical phenomenaChemical Reviews, 1993
- Application of RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvationJournal of the American Chemical Society, 1993
- Structure of a cyclophane host moleculeActa crystallographica Section B, Structural science, crystal engineering and materials, 1993
- Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanicsJournal of Computational Chemistry, 1990
- The MIDAS display systemJournal of Molecular Graphics, 1988
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983