caa a22 4500 469059265 CHVBK 20180323132852.0 cr unu---uuuuu 170328e19920101xx s 000 0 eng 10.1007/BF01053854 doi (NATIONALLICENCE)springer-10.1007/BF01053854 Free energy perturbation simulations of cation binding to valinomycin [Elektronische Daten] [George Eisenman, Osvaldo Alvarez, Johan Aqvist] Experimental values of the free energies of cation binding to the cyclic depsipeptide molecule, valinomycin, obtained from Pedersen-type salt extraction measurements, provide data against which it is possible to test the adequacy of the procedures and force fields of the molecular dynamics algorithms, MOLARIS and GROMOS. These data are then used to assess appropriate values for the partial charges of the ester carbonyl oxygen and carbon. Valinomycin was chosen because it has only one kind of ion-binding ligand and because the cation is sufficiently enfolded by the molecule in the ion-complexes that the overall size and shape of the complex is virtually the same regardless of the species of cation bound. For such an ‘isosteric complex', the experimentally measured selectivities are sufficiently similar in a wide variety of solvent environments that thedifferences in free energies measured between the different ion-valinomycin complexes by two-phase salt extraction experiments into dichloromethane can be taken as equivalent to the differences in free energies in vacuo. Thesedifferences were therefore compared with those computed for ion-valinomycin complexationin vacuo by Free Energy Perturbation/Molecular Dynamics (FEP/MD) simulations using the MOLARIS and GROMOS programs. Starting with a set of Lennard-Jones 6-12 parameters for the monovalent cations assessed for aqueous solution we explored the effect of varying the partial charges of the ester carbonyl ligands on binding free energy differences (i.e. the selectivity) among Na, K, Rb, and Cs. The computed selectivity was found to depend strongly on the value of partial charge, following a typical ‘Eisenman Selectivity Pattern' in which the correct selectivity sequence and magnitude occurred only over a very narrow range of partial charge (around 0.33 and 0.6 for the standard carbonyls of MOLARIS and GROMOS, respectively). Using MOLARIS we explored the effect of varying the size of the ester carbonyl ligands by comparing the standard carbonyl of MOLARIS with the somewhat smaller carbonyls of GROMOS and found an equally satisfactory ability to reproduce the experimental data with a partial charge value of 0.41. These results validate the use of both the MOLARIS and GROMOS force fields as starting points for quantitative calculations of ion-binding in more complex molecules (e.g., ion-binding sites and channels in proteins). Kluwer Academic Publishers, 1992 Molecular dynamics nationallicence free energy perturbation simulations nationallicence ion-binding ion-complexation nationallicence ion-selectivity nationallicence ion-carbonyl bond angles and distances nationallicence valinomycin selectivity nationallicence MOLARIS nationallicence GROMOS nationallicence Pedersen two-phase salt-extraction nationallicence Eisenman selectivity sequences nationallicence Lennard-Jones parameters for ions nationallicence isostericity nationallicence Eisenman George Department of Physiology, UCLA Medical School, 90024-1751, Los Angeles, CA, USA aut Alvarez Osvaldo Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile aut Aqvist Johan Department of Molecular Biology, Uppsala Biomedical Center, S-75124, Uppsala, Sweden aut Journal of inclusion phenomena and molecular recognition in chemistry Kluwer Academic Publishers 12/1-4(1992-01-01), 23-53 0923-0750 12:1-4<23 1992 12 10847 https://doi.org/10.1007/BF01053854 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF01053854 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Eisenman George Department of Physiology, UCLA Medical School, 90024-1751, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Alvarez Osvaldo Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile aut NATIONALLICENCE 700 1- Aqvist Johan Department of Molecular Biology, Uppsala Biomedical Center, S-75124, Uppsala, Sweden aut NATIONALLICENCE 773 0- Journal of inclusion phenomena and molecular recognition in chemistry Kluwer Academic Publishers 12/1-4(1992-01-01), 23-53 0923-0750 12:1-4<23 1992 12 10847 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer