Alkali Metal Ion Binding to Amino Acids Versus Their Methyl Esters: Affinity Trends and Structural Changes in the Gas Phase Jody M. Talley, [a] Blas A. Cerda, [a, c] Gilles Ohanessian,* [b] and Chrys Wesdemiotis* [a] Abstract: The relative alkali metal ion (M  ) affinities (binding energies) be- tween seventeen different amino acids (AA) and the corresponding methyl esters (AAOMe) were determined in thegasphasebythekineticmethodbased onthedissociationofAA±M  ±AAOMe heterodimers (M  Li,Na,K,Cs).With the exception of proline, the Li  , Na  , and K  affinities of the other aliphatic aminoacidsincreaseintheorderAA < AAOMe, while their Cs  affinities gen- erally decrease in this direction. For aliphatic b-amino acids, which are par- ticularly basic molecules, the order AA > AAOMe is already observed for K  .Prolinebindsmorestronglythanits methyl ester to all M  except Li  . Ab initio calculations on the M  complexes of alanine, b-aminoisobutyric acid, pro- line,glycinemethylester,alaninemeth- yl ester, and proline methyl ester show that their energetically most favorable complexes result from charge solvation, except for proline which forms salt bridges.Themoststablemodeofcharge solvationdependsontheligand(AAor AAOMe) and, for AA, it gradually changes with metal ion size. Esters chelate all M  ions through the amine andcarbonylgroups.Aminoacidscoor- dinate Li  and Na  ions through the amine and carbonyl groups as well, but K  andCs  ions are coordinated by the O atoms of the carboxyl group. Upon consideration of these differences in favoredbindinggeometries,thetheoret- ically derived relative M  affinities be- tweenaliphaticAAandAAOMearein good overall agreement with the above givenexperimentaltrends.Themajority ofsidechainfunctionalizedaminoacids studiedshowexperimentallytheaffinity order AA < AAOMe for all M  ions, which is consistent with charge solva- tion. Deviations are only observed with the most basic amino acids lysine and arginine, whose K  (for arginine) and Cs  complexes (for both) follow the affinityorderAA > AAOMe.Thelatter ranking is attributed to salt bridge for- mation. Keywords: alkali metals ¥ amino acids ¥ amino acid esters ¥ charge solvation ¥ kinetic method ¥ mass spectrometry ¥ salt bridges Introduction In aqueous media, all common a-amino acids are known to adoptzwitterionicstructureswithdeprotonatedcarboxyland protonated amine (or basic side chain) termini. [1] Although these zwitterions are inherently less stable than the corre- sponding canonical (free acid) tautomers, they interact much more strongly with water than their uncharged tautomers, therebybecomingthelowestenergystructuresinsolution.In contrast, gas-phase a-amino acids exist as free acids because of the absence of stabilizing intermolecular interactions. This has been unequivocally shown for glycine (Gly) [2±7] and phenylalanine (Phe) [8] as well as for the most basic amino acid, arginine (Arg). [9] This indicates that the carboxyl group is not sufficiently acidic for spontaneous intramolecular deprotonation even by the quite basic guanidine group of arginine. [10] Theintrinsicstabilityofaminoacidzwitterionsisincreased significantlybycomplexationwithalkalimetalions.Thus,the glycinezwitterionis60±80kJmol 1 less stable than the free acid according to theory; [4, 11] however, the energy difference between zwitterionic and canonical (i.e. charge-solvated) [glycineNa]  tautomers is reduced to only 8±12kJmol 1 , primarily because of the formation of a salt bridge between the carboxylate terminus and the metal cation. [11±14] For [argininealkali metal]  complexes, the relative energy between zwitterionic and charge-solvated isomers depends onthemetalion(M  ). Density functional theory (DFT) and kinetic experiments on the dissociation of [ArgM]  carried out by Williams etal., [15] as well as our assessment of the Arg±M  binding energies relative to those of pertinent [a] Dr.C.Wesdemiotis,J.M.Talley,Dr.B.A.Cerda Department of Chemistry, The University of Akron Akron, OH 44325-3601 (USA) Fax:( 1)330-972-7370 E-mail:wesdemiotis@uakron.edu [b] Dr. G. Ohanessian Laboratoire des Me ¬canismesRe ¬actionnels URA1307duCNRS Ecole Polytechnique, 91128 Palaiseau Cedex (France) Fax:( 33)1-6933-3041 E-mail:gilles@dcmr.polytechnique.fr [c] Dr.B.A.Cerda Present address: PerkinElmer Life Sciences 3985 Eastern Road, Norton, Ohio 44203-6215 (USA) FULL PAPER Chem. Eur. J. 2002, 8,No. 6 ¹ WILEY-VCHVerlagGmbH,69451Weinheim,Germany,2002 0947-6539/02/0806-1377 $ 17.50+.50/0 1377