DOI: 10.1002/cphc.201200964

Interaction Modes and Absolute Affinities of a-AminoAcids for Mn2 + : A Comprehensive PictureM. Hassan Khodabandeh,[a] Hamid Reisi,[a] Mehdi D. Davari,[c] Karim Zare,[a]

Mansour Zahedi,*[a] and Gilles Ohanessian*[b]

1. Introduction

Manganese is involved in many biochemical processes throughits role as a cofactor in the activation of several classes of en-zymes, including carboxylases, dehydrogenases, and synthetas-es.[1–4] As such it is involved in, for example, the metabolism ofcarbohydrates and the synthesis of thyroid hormones. Overall,manganese import, transport, accumulation, sensing, and con-trol pathways are important for all organisms, and of uniqueimportance for oxygenic photosynthetic organisms due totheir role in the catalysis of water oxidation by photosystem IIcomplexes.[2, 5] The fruitful appearance of manganese in theRNA structure and biological catalysts,[6, 7] and its toxic role insome proteins such as prion,[8–10] are all evidence of the impor-tance of this metal in living systems. Thus, understanding in

detail the local interactions between this metal ion and its en-vironment in proteins or peptides[11, 12] is a focus of high cur-rent interest. The present work aims at providing a significantstep forward in this endeavor.

In addition to this biochemical importance, there is a vast in-terest within the mass spectrometry community in the systemsincluding metal-cation linkage to amino acids (AAs) and pep-tides, because it has been proven that coordination of transi-tion-metal ions is a useful tool for the investigation of the pri-mary structures of peptides.[13–15] One of the most importantfactors influencing the manganese ion’s location in the hydro-phobic segment of a protein has been regarded as the intrinsicstrengths of the bonds that are possibly formed between theionized metal and bonding sites of protein. Such an importantthermochemical factor can be investigated with a high experi-mental corroboration in the gaseous state, in which interven-ing and complicating solvent effects are avoided.[12, 16]

Theoretical methods have been extensively and successfullyutilized for studying cationized peptides and a-AAs in the gasphase.[16–84] Such studies have revealed that in numerous cases,a large resemblance exists between gas-phase bonding ofthese complexes and the interactions seen in the aqueous so-lution phase for the inner segment of proteins. In any case,thermochemical as well as structural data obtained by theoreti-cal calculations provide building blocks to understand thenature of metal ion–protein interaction in the condensedphase.

Despite the high significance of manganese, only a few MnII

cation complexes with AAs,[34, 58, 84] and small molecules,[85–89]

Manganese is involved as a cofactor in the activation of nu-merous enzymes as well as the oxygen-evolving complex ofphotosystem II. Full understanding of the role played by theMn2+ ion requires detailed knowledge of the interactionmodes and energies of manganese with its various environ-ments, a knowledge that is far from complete. To bring de-tailed insight into the local interactions of Mn in metallopepti-des and proteins, theoretical studies employing first-principlesquantum mechanical calculations are carried out on [Mn-amino acid]2 + complexes involving all 20 natural a-aminoacids (AAs). Detailed investigation of [Mn-serine]2 +

, [Mn-cys-teine]2 + , [Mn-phenylalanine]2 + , [Mn-tyrosine]2 + , and [Mn-tryp-tophan]2+ indicates that with an electron-rich side chain, the

most stable species involves interaction of Mn2+ with carbonyloxygen, amino nitrogen, and an electron-rich section of theside chain of the AA in its canonical form. This is in sharp con-trast with aliphatic side chains for which a salt bridge isformed. For aromatic AAs, complexation to manganese leadsto partial oxidation as well as aromaticity reduction. Despitemultisite binding, AAs do not generate strong enough ligandfields to switch the metal to a low- or even intermediate-spinground state. The affinities of Mn2 + for all AAs are reported atthe B3LYP and CCSD(T) levels of theory, thereby providing thefirst complete series of affinities for a divalent metal ion. Thetrends are compared with those of other cations for which af-finities of all AAs have been previously obtained.

[a] M. H. Khodabandeh, H. Reisi, Prof. K. Zare, Prof. M. ZahediDepartment of Chemistry, Faculty of SciencesShahid Beheshti UniversityG.C. , Evin 19839-6313, Tehran (Iran)Fax: (+ 98) (21) 22401765E-mail : m-zahedi@cc.sbu.ac.ir

[b] Prof. G. OhanessianLaboratoire des M�canismes R�actionnelsD�partement de Chimie, Ecole Polytechnique, CNRS91128 Palaiseau Cedex (France)Fax: (+ 33) (0)1 69 33 48 03E-mail : gilles.ohanessian@polytechnique.fr

[c] Dr. M. D. DavariTheoretical and Computational Biophysics DepartmentMax Planck Institute for Biophysical ChemistryAm Fassberg 11, 37077 Goettingen (Germany)

Supporting information for this article is available on the WWW underhttp://dx.doi.org/10.1002/cphc.201200964.

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have been investigated. In our previous work, manganesecomplexation with the simplest AA, glycine,[58] and its interac-tion with lysine and histidine,[84] have been thoroughly investi-gated. The aforementioned two studies were mainly focusedon an accurate search on the potential energy surface (PES),which ultimately resulted in the true nature of the metal–AAbonding and thermodynamic properties.

In the work reported herein, however, the main attentionhas been paid to obtaining an overall picture of the interactionof Mn2 + with all 20 AAs. If a metal cation such as Mn2+ is at-tached to an AA, several low-energy isomers can be formed,which fall into two broad categories: 1) charge solvated (CS),in which the metal charge is stabilized by interaction with one,two, or more electron-rich site(s) of the AA in its neutral form;and 2) salt bridges (SBs), in which the metal charge interactsdirectly with the carboxylate group of the AA in its zwitterionicform. A point of special interest is to understand the relativestability of SB and CS isomers. The manganese ion interactionswith serine and cysteine are first detailed to understand theeffect of their side-chain heteroatoms. Then cation–p interac-tions in the formation of the most stable structures of[Mn-AAarom]2 + (AAarom = Phe, Tyr, and Trp) are investigated andcompared with those reported previously with some transi-tion- and alkali-metal ions.[57, 71, 90, 100] IR spectra are also reportedfor the most stable conformers of all species. Based on thesedetailed case studies, the most stable forms of all AA com-plexes with Mn2+ are described in the final section. In all casesit is found that the high spin state of Mn2 + is retained, despitemany cases of tridentate binding of the AA to the metal ion.Stabilizing side chain–metal cation interactions can be largeenough that CS species are found to be more stable than theirSB isomers in all cases except the aliphatic AAs. Absolute AAaffinities of the Mn2 + cation to the 20 AAs are reported byusing accurate quantum chemical methods, thus yielding anaffinity order that will be useful in understanding the competi-tion of sites for Mn2 + capture in protein binding sites. Thetrends can then be compared to the few obtained previouslyfor other metal cations.

Computational Details

Optimized molecular geometries and the corresponding harmonicvibrational frequencies were obtained by employing a nonlocalhybrid three-parameter B3LYP density functional method.[101–103]

Previous theoretical calculations on analogous systems includingvarious metal complexes of AAs,[104–107] as well as recent studies onMn2 +-glycine and Mn2 +-lysine complexation,[58, 84] have revealedthat B3LYP serves as an effective method for studying transition-metal ligand systems. In the present cases, in which electron deloc-alization is assumed to be important, a comparative study ofB3LYP with the highly correlated CCSD(T) method again provedthe fruitfulness of the former method. Moreover, to justify resultsthat have been achieved for the desired systems by the DFTmethod, calibration calculations were carried out on the moststable conformers by employing the single and double coupled-cluster method with a perturbational estimate of the connectedtriple excitations CCSD(T),[108] including all valence electrons. To ex-plore the conformation space of this kind of system, an initial con-

formational search of the Na+-AA complexes was performed onlyto model the electrostatic interaction of the metal cation with theAA, due to the PM3[109, 110] semiempirical method not being para-meterized for Mn. After obtaining the models, Na was replaced byMn for subsequent optimizations.[57] The 6-31G(d,p) basis set,[111, 112]

with Cartesian d-type functions (6D), was used for all atoms in ge-ometry optimizations as well as vibrational frequency calculations.These frequencies were scaled by using a single scaling factor of0.96 in the entire IR range. Results obtained by utilizing this basisset showed close correspondence with larger ones as validatedpreviously elsewhere.[58, 84] To calculate energies and molecularwave functions, the Wachters [14s11p6d3f/8s6p4d1f] basis set forMn[113, 114] and the 6-31 + + G(d,p) basis set with spherical d-typefunctions (5D) for other atoms were employed.

[115, 116] Hereafter, theaforementioned basis sets are noted as “basis” wherever appropri-ate. All DFT calculations were performed with the Gaussian 09 suiteof programs.[117] CCSD(T) computations were performed by usingthe MOLPRO 2010.1 package.[118] Thermodynamical corrections as-suming ideal gas, unscaled harmonic vibrational frequencies, andrigid-rotor approximation resulting from a standard statisticalmethod were obtained.[119] Average atomic charges and spin densi-ties were obtained with the natural population analysis of Wein-hold et al.[120, 121] The calculated results for spin contamination aswell as wave function stability were checked and data revealedthat contamination was less than 0.1. This low value did not havemuch effect on the energy values of unrestricted wave functions,and due to them being closer to the exact values, unrestricted for-malism was utilized in this study.

2. Results and Discussion

As stated above, except for a few concise studies,[34, 58, 84] limitedeffort has been devoted to detailed investigation on structuresand bonding energies of all AAs with the doubly charged man-ganese cation. All possible spin states have been taken into ac-count as in our previous studies.[58, 84] It was shown that com-plexes resulting from interaction of doublet and quartet elec-tronic spin states of Mn2 + with glycine, histidine, and lysineare unstable relative to those of the sextet electronic spinstate. For this reason, the former two spin states are of low im-portance. We start by considering details of Mn2+ complexa-tion with serine and cysteine. These two only differ in theirside-chain termination, a hydroxyl group for the former andthiol for the latter. At the conclusion of this section, bondingenergies and vibrational spectra of the most stable complexesare reported and discussed.

To shed light on the aromatic ring effect and cation–p inter-actions with the side chain, and arriving at the stable structureand determining AA bonding energy with the cation, Mn2 +

complexation with phenylalanine, tyrosine, and tryptophanwere investigated. Having performed a complete analysis ofthe most important vibrations of the latter complexes, thenext section is assigned to introduction of the most stablecomplexes of all remaining natural AAs with the manganesecation. With a brief discussion on the structure of the afore-mentioned species, the AA affinity of the doubly charged man-ganese ion is reported and discussed for all AAs.

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2.1. [Mn-Serine]2+ and [Mn-Cysteine]2 + Systems

Based on the theoretical investigations carried out sofar,[30, 122–124] useful information was obtained regarding the PESconformational search for free serine and cysteine. These twoAAs include C–O or C–S and C–C rotors in addition to those ofglycine. Moreover, due to possible formation of more intramo-lecular hydrogen bonds by the hydroxyl group in serine or thethiol group in cysteine, they possess much more complicatedconformational space. Gronert and O’Hair[122] have reportedmore than 30 stable conformers in a 4 kcal mol�1 range. Similarresults with eight conformers in a range less than about2.5 kcal mol�1 were found in the present work. Regarding suchresults, prediction of all stable complexation modes of thesetwo AAs with metal cations is not possible. Our previous re-sults for glycine, histidine, and lysine complexation with themanganese cation,[58, 84] as well as those of other AAs with vari-ous metal ions such as Cu+ ,[30] can be the best guide forchoosing the starting structures. In the complexation study ofglycine,[58] it was realized that monodentate species are of lessimportance among stable structures. Thus, the first clue sug-gests considering complexes with higher than monodentatecoordination. One would naturally expect bonding from elec-tron-rich sites with high donor capability, such as carbonyloxygen, terminal nitrogen of the backbone group, and heter-oatoms in the side chain, to be of higher importance. Anotherkey could be regarded as constructing the starting structuressuch that they include the highest possibility for intramolecularhydrogen bonding. Less ligand deformation relative to that ofits free state would be another lead in making a more stablecomplex as a starting point.

Accounting for all the above points, 14 of the most stablestructures were chosen among the search span shown inFigure 1 and were utilized for further study. Resemblance of allstructures for both systems is the reason for presentinga single figure. Among the species of Figure 1, CS structures ofwhich 1S and 5S are the most important tridentate cases weresearched first. Similar to the glycine, histidine, and lysinestudy,[58, 84] all possible combina-tions of heteroatoms to comeup with bidentate coordinationwere examined. Minima struc-tures 8S to 13S of Figure 1 arethe result of such a search. Final-ly, binding of Mn2 + to variouszwitterionic forms of serine andcysteine isomers to form SB spe-cies were considered. The latterprobe led to the remaining spe-cies of Figure 1, namely 2S, 3S,4S, 6S, 7S, and 14S. To compareenergies and some geometricalparameters of all the above spe-cies, Tables 1 and 2 as well asFigure 1 summarize the B3LYPcomputed results. For the sakeof convenience, the energy or-

dering of Table 1 for [Mn-Ser]2+ complexes is in accord withthe corresponding species’ numbering system of Figure 1.

Some notations used in Tables 1 and 2 are as follows:MnS1S and MnC1S indicate [Mn-Ser]2+ and [Mn-Cys]2 + com-plexes, respectively. The number stands for the complexnumber and the terminating letter S shows the sextet electronspin state, which has been proven to be the most stable spinstate.[58, 84] Some more labels employed within the text andtables are: Nt amino nitrogen, OC carbonyl oxygen, OOH hydrox-

Figure 1. Optimized geometry of several [Mn-Serine]2 + and [Mn-Cysteine]2+

isomers. Distances are in �, with [Mn-Cysteine]2 + values in parentheses.

Table 1. Relative energies [kcal mol�1] of [Mn-serine]2 + isomers and population analysis at the B3LYP/basislevel.

Mn natural populationStructure Coordination State DE 4s 3d 4p q (Mn) Spin (Mn)

MnS1S Nt, OC, OOH26A 0.0 0.13 5.15 0.09 1.62 4.86

MnS2S O, O� 6A 11.0 0.14 5.16 0.04 1.66 4.92MnS3S O, O� 6A 13.2 0.15 5.15 0.04 1.66 4.92MnS4S OC,O� 6A 15.3 0.12 5.22 0.06 1.59 4.82MnS5S Nt, OOH1, OOH2

6A 17.0 0.13 5.15 0.09 1.64 4.88MnS6S O, O� , OOH2

6A 19.2 0.12 5.17 0.07 1.63 4.85MnS7S O, O� 6A 21.7 0.15 5.16 0.04 1.65 4.92MnS8S Nt, OC

6A 22.1 0.14 5.14 0.05 1.66 4.91MnS9S OC, OOH2

6A 28.0 0.09 5.15 0.06 1.69 4.87MnS10S Nt, OOH2

6A 29.2 0.14 5.13 0.05 1.68 4.92MnS11S Nt, OC

6A 29.5 0.13 5.14 0.05 1.67 4.90MnS12S Nt, OOH2

6A 32.5 0.15 5.13 0.05 1.67 4.93MnS13S Nt, OOH1

6A 40.3 0.13 5.13 0.05 1.69 4.91MnS14S O, O� 6A 41.2 0.16 5.15 0.04 1.65 4.94

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yl oxygen, and O� carboxylate oxygen, all of which correspondto the AA backbone. OOH2 is side-chain hydroxyl oxygen, O�OH2

is the OOH2 anion, and SSH and S� are the thiol and thiolatesulfur, respectively.

Energy comparison of various species from Tables 1 and 2(without zero-point energy considered) reveals that the moststable configuration is the 1S structure. A large energy gap be-tween this and the remaining species ensures that 1S is theequilibrium stable structure for [Mn-Ser]2 + and [Mn-Cys]2 +

complexes. Such isomers include metal cation interaction withcarbonyl oxygen, amino nitrogen, and hydroxyl oxygen of theserine side chain or thiol sulfur of cysteine (Figure 1). The 1Sstructures with both AAs are similar and their only notable dif-ference relates to the side chain’s complexation mode. In theserine case, the alcohol hydrogen resides almost in the MnOCplane (Figure 1, 1S). However, the thiol hydrogen in metal–cys-teine is completely out of the MnSC plane, which makes a dihe-dral angle HSCMn of about 1038 (see Figure on page 24 in theSupporting Information). This fact can be attributed to thehigh polarization of the lone pair on sulfur and its influence onthe type of interaction with the metal cation. The same effecthas been reported in Cu+ complexation,[30] whereas the natureof the interaction of hydroxyl oxygen with the metal cation isgoverned by charge-dipole electrostatics. Paying close atten-tion to the cation charge in Tables 1 and 2 reveals that electrontransfer from ligand to metal is larger in MnC1S than inMnS1S, such that charge reduction on the metal cation islarger in the former than in the latter by about 0.14, thus em-phasizing the larger thiol sulfur than hydroxyl oxygen polariza-tion.

Structure 2S of Figure 1 with SB shape is due to bidentateinteraction of the carboxylate group in serine and cysteine tometal cation with the amine being protonated. In 2S, no inter-action between metal and hydroxyl or thiol group exists. Thepresence of two intramolecular hydrogen bonds, namely H2N+

�H···O� and H2N+�H···O(S)H, has resulted in a more stable con-figuration than most other species. Yanez et al.[125] have report-ed similar hydrogen-bonding interactions in some water trim-

ers. Looking closer at this struc-ture indicates that the coordina-tion lengths of carboxylateoxygen atoms to Mn2 + areslightly asymmetric (about 0.03–0.04 � difference). This can becaused by hydrogen bonding onthe oxygen linked to the metal,which leads to reduction of itspartial charge and therefore de-creases its coordination tenden-cy. Another point regarding 2Sspecies is that the coordinationlengths are almost identical inserine and cysteine. Such an ob-servation would be expected be-cause the side group is far fromthe coordination center, thushaving no influence on coordi-

nation length. Considering the relative energy of the 2S struc-ture in Tables 1 and 2 reveals that it assumes second rank for[Mn-Ser]2 + and fifth for [Mn-Cys]2+ , and is about 11 and15.7 kcal mol�1 higher than the most stable isomer, respective-ly. Such a difference of 2S stability rank is mostly due to thestronger intramolecular hydrogen bond H2N+�H···OH in serinerelative to H2N+�H···SH in cysteine. A shorter H-bonding inter-action length of about 0.4 � in serine than in cysteine, as wellas observation of the fact that the O�H bond length has elon-gated due to complexation whereas the S�H bond length re-mains almost intact, are in accord with the above argument.

The third most stable structure of Figure 1, labeled 3S withSB shape, is similar to 2S as far as coordination type is con-cerned. The only major difference between them relates to themode of intramolecular hydrogen bonding with weakenedH2N+�H···O� and strengthened H2N+�H···O(S)H interactions.Moreover, comparison of 2S and 3S suggests less distortion ofthe zwitterionic AA in the latter species. Accumulating theabove energetic contributions results in 3S of [Mn-Cys]2 +

being more stable than 2S by about 1.3 kcal mol�1. The nextminimum, namely 4S, with SB shape seems interesting in viewof its coordination. With migration of an H atom from the side-chain hydroxyl oxygen or thiol sulfur to terminal nitrogen, andtherefore a strong bidentate interaction from the oxygen orsulfur anion of the side chain and carbonyl oxygen of thebackbone group with the metal cation, 4S is evolved. This spe-cies assumes fourth position in the [Mn-Ser]2 + and second inthe [Mn-Cys]2 + stability rank. Inclusion of three intramolecularhydrogen bonds in the 4S moiety can be a substantial factorin stabilization of this structure (see Figure 1). Looking at thecharge on the metal cation of 4S in the [Mn-Cys]2+ system incomparison with other species, maximum charge depletionand transfer has been evidenced. Thus, second rank for the 4Scase and its extraordinary stability can also be accounted forby extreme polarization of the electron cloud in sulfur(Tables 1 and 2). As is evident from Table 2, on changing thefunctional group from OH to SH, the energy gap betweenglobal CS and global SB species decreases to about 5.2 kcal

Table 2. Relative energies [kcal mol�1] of [Mn-cysteine]2 + isomers and population analysis at the B3LYP/basislevel.

Mn natural populationStructure Coordination State DE 4s 3d 4p q (Mn) Spin (Mn)

MnC1S Nt, OC, S 6A 0.0 0.21 5.18 0.12 1.48 4.86MnC2S O, O� 6A 15.7 0.14 5.15 0.04 1.66 4.92MnC3S O, O� 6A 14.4 0.15 5.16 0.04 1.65 4.92MnC4S OC, S� 6A 5.2 0.27 5.25 0.10 1.37 4.85MnC5S Nt, OOH, S 6A 17.7 0.22 5.17 0.12 1.47 4.88MnC6S O, O� , S 6A 14.5 0.19 5.18 0.09 1.52 4.86MnC7S O, O� 6A 22.0 0.16 5.15 0.04 1.64 4.94MnC8S Nt, OC

6A 22.9 0.15 5.15 0.05 1.65 4.90MnC9S OC, S 6A 27.9 0.22 5.18 0.08 1.52 4.88MnC10S Nt, S 6A 28.9 0.26 5.16 0.07 1.50 4.93MnC11S Nt, OC

6A 29.5 0.14 5.15 0.05 1.65 4.89MnC12S Nt, S 6A 32.5 0.28 5.16 0.07 1.49 4.95MnC13S Nt, OOH

6A 43.1 0.14 5.15 0.05 1.66 4.90MnC14S O, O� 6A 39.3 0.16 5.17 0.04 1.63 4.91

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mol�1. Such a gap for Ca2+ [21] is so low that a mixture of bothCS and SB moieties at high temperatures has been predicted.

Seeking PESs for more conformational minima led to twostructures of three-coordination mode, 5S and 6S. The 5S CSisomer resembles the 1S moiety with the only difference beingthat instead of carbonyl oxygen, it is the backbone hydroxyloxygen that is linked to the metal. It has been shown that co-ordination of hydroxyl oxygen to the metal cation is weakerthan that of carbonyl oxygen.[58, 84] Structure 6S is another SB-type structure arising from interaction of carboxylate oxygenatoms and side-chain hydroxyl oxygen in serine or thiol’s sulfurwith Mn2+ . It was expected that, due to strong electrostatic in-teractions, the 6S moiety would be one of the most stable spe-cies. However, as is evident from Figure 1, due to large distor-tion of the zwitterionic ligand, the 6S moiety has lost stabilityto a large extent. In terms of configurational energy stability,5S assumes fifth and sixth rank whereas 6S adopts sixth andfourth rank in [Mn-Ser]2+ and [Mn-Cys]2+ , respectively. All re-maining species, which are of less importance than those dis-cussed so far due to lying no less than 21 kcal mol�1 above themost stable isomer, are shown as Figure S1 in the SupportingInformation. However, relative energies as well as populationanalysis of the aforementioned species are summarized inTables 1 and 2 for comparison with others.

By comparison of the results in Table 2 with similar data inTable 1, one will realize that if interaction sites with the metalcation are oxygen or nitrogen atoms, hybridization of metald orbitals with 4s and 4p orbitals occurs to a lesser extent thanif one of the sites is sulfur. This point is apparent from theextent of metal cation charge depletion and natural popula-tion data for relevant cases of Tables 1 and 2. In the absence ofsulfur in the coordination center, the metal charge decreasesto an average of 1.65 whereas, if one of the metal interactionsites involves sulfur, metal positive-charge depletion is moresensible such that its average charge becomes less than 1.5. Ifthe sulfur anion is coordinated to the metal cation, chargetransfer is even larger and the metal charge decreases by asmuch as 0.63 (Table 2). The above observation is an indicationof the increase in covalent-type contribution to these site in-teractions with the metal,[34] even though the major energeticcomponent of these interactions remains electrostatic.

IR spectra computed for the most stable structures 1S for[Mn-Ser]2 + and [Mn-Cys]2 + are illustrated in Figure S2, in whichB3LYP/6-31G(d,p) frequencies are scaled by 0.96 in the entirespectral range.

Thermochemical Analysis of [Mn-Ser]2 + and [Mn-Cys]2 +

Systems

Calculated parameters of De, D0, DU0298, DH0

298, and DG0298 for

the most stable structures of [Mn-Ser]2 + and [Mn-Cys]2+ sys-tems are summarized in Tables 3 and 4, respectively. Ourlowest-energy free AAs corroborate well with those in thework of Alonso et al.[123, 124] The global minimum for cysteine isthe same as that reported elsewhere.[123] Regarding conforma-tional search of serine at the B3LYP/6-31G(d,p) level, our globalminimum is lower than that given in reference [124] by about

0.8 kcal mol�1. Due to employing a relatively large basis set,the basis set superposition error has been ignored in compar-ing the results compiled in Tables 3 and 4. Interaction energies(De) without considering zero-point energy at the B3LYP levelusing the “basis” basis set are 195.4 and 194.7 kcal mol�1 for[Mn-Ser]2 + and [Mn-Cys]2 + systems, respectively. These resultsare in accord with those obtained with the high-level coupledcluster CCSD(T) method, especially for the cysteine case. Suchgood agreement was also found in previous work for manga-nese interaction with histidine and lysine.[84] A change in ser-ine’s hydroxyl oxygen interaction site to cysteine’s sulfur re-sults in a decrease of about 4.9 kcal mol�1 interaction energywith the metal cation at the CCSD(T) level. Thus one can con-clude that, because the stable structures for both systems aresimilar, the difference of side-chain contribution to interactionenergy with Mn2+ between serine and cysteine is about4.9 kcal mol�1. Next, the DU0

298 value at the CCSD(T) level canbe introduced as manganese affinity for AA, which is similar tothe DH0

298 value, including thermal but not DnRT corrections.Due to the neglect of experimental pressures, the DnRT valueis minute such that the values of DU0

298 and DH0298 agree to

a first decimal place (see Tables 3 and 4).

Table 3. Mn2+–serine interaction energies [kcal mol�1] in [Mn-serine]2 + .

Interaction energies Method Mn2 + , 6A Cu+ [d] Na+ [e]

De B3LYP[a] 202.8B3LYP[b] 195.4CCSD(T) 195.8

D0 194.0[c]

DU0298 192.5[c] 67.4

DH0298 192.5[c] �47.8

DG0298 195.2[c]

[a] Determined at the B3LYP/6-31G(d,p)//B3LYP/6-31G(d,p) level. [b] Deter-mined at the B3LYP/basis//B3LYP/6-31G(d,p) level. [c] Determined at theCCSD(T)/basis//B3LYP/6-31G(d,p) level and after taking into considerationcorrections determined at the B3LYP/6-31G(d,p) level. [d] Value takenfrom ref. [30] at the MP2 level. [e] Value taken from ref. [71] at the MP2level.

Table 4. Mn2+–cysteine interaction energies [kcal mol�1] in [Mn-cys-teine]2+ .

Interaction energies Method Mn2 + , 6A Co2 + [d] Zn2+ [e] Cd2 + [e]

De B3LYP[a] 198.1B3LYP[b] 194.7CCSD(T) 190.9

D0 188.9[c]

DU0298 187.4[c]

DH0298 187.4[c] 237.7 214.5 177.5

DG0298 189.8[c]

[a] Determined at the B3LYP/6-31G(d,p)//B3LYP/6-31G(d,p) level. [b] Deter-mined at the B3LYP/basis//B3LYP/6-31G(d,p) level. [c] Determined at theCCSD(T)/basis//B3LYP/6-31G(d,p) level and after taking into considerationcorrections determined at the B3LYP/6-31G(d,p) level. [d] Value takenfrom ref. [83] at the B3LYP level. [e] Values taken from ref. [77] at theB3LYP level.

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Comparison of the cysteine af-finity of Mn2 + shows a decreasein its value relative to Co2 + [83]

and Zn2+ [77] cations but suggestsan increase in its affinity relativeto Cd2 + .[77] This trend correlateswell with that of the metal ionicradius, which controls the mag-nitude of electrostatic and polar-ization interactions.

2.2. [Mn-Phenylalanine]2+ ,[Mn-Tyrosine]2 + , and[Mn-Tryptophan]2 + Systems

Complexation of histidine as anaromatic AA has been reportedearlier.[84] To investigate theeffect of the side-chain aromaticring in the coordination process,phenylalanine (Phe), tyrosine(Tyr), and tryptophan (Trp) areconsidered herein. In their neu-tral state, all three AAs includea hydrogen bond between thecarboxyl group proton andamino nitrogen as their moststable conformers.[57, 98, 126, 127] Inour conformational search theaforementioned structures werefound to be the most stableconformers. These species wereemployed for calculation of theirinteraction energy with theMn2+ ion. It is expected that,due to the presence of an aro-matic ring, cation–p interactionsassume a good share of metalion affinity. By seeking the PES,the most stable configuration forall three species showed p–ringdirect interaction with the metalcation besides that of the back-bone group. This observation iscontrary to the results reportedfor the same AA interaction withCu2+ , in which, due to their p sy-stem having a positive radicalcharacter, repulsion between AAand metal cation has been evi-denced.[57] To provide a general picture of bonding and ener-getics, we describe below the most stable moiety, a CS specieswithout cation–p interaction, as well as a SB structure for eachcomplex.

Figure 2 depicts these three systems with selected geometri-cal parameters. Table 5 summarizes the relative energies with-out zero-point energy correction. Analogous to systems found

for aromatic AAs interacting with Cu+ ,[57] Ag+ ,[90] and alkalimetal ions,[92–100] Mn2 + interacts with the amino nitrogen, car-bonyl oxygen, and aromatic p group of neutral AA side chainsin all three cases. The resulting complexes with a CS-typesystem are designated as MnPhe1S, MnTyr1S, and MnTrp1S,and are illustrated in Figure 2. The aforementioned type ofstructure has not been observed in the Cu2 + complex.[57] Also,

Figure 2. Optimized geometry of several [Mn-Phenylalanine]2 + , [Mn-Tyrosine]2 + , and [Mn-Tryptophan]2+ isomers.Distances are in �.

Table 5. Relative energies [kcal mol�1] of isomers of [Mn-phenylalanine]2+ , [Mn-tyrosine]2 + , and [Mn-trypto-phan]2 + and population analysis at the B3LYP/basis level.

Mn natural populationStructure Coordination State DE 4s 3d 4p q (Mn) Spin (Mn)

MnPhe1S Nt, OC,2hC 6A 0.0 0.17 5.21 0.18 1.41 4.79

MnPhe2S Nt, OC6A 30.8 0.14 5.16 0.06 1.64 4.89

MnPhe3S O, O� 6A 20.0 0.16 5.16 0.04 1.63 4.92

MnTyr1S Nt, OC,2hC 6A 0.0 0.19 5.21 0.16 1.42 4.80

MnTyr2S Nt, OC6A 28.7 0.19 5.28 0.05 1.47 4.71

MnTyr3S O, O� 6A 21.2 0.28 5.13 0.06 1.53 4.88

MnTrp1S Nt, OC,2hC 6A 0.0 0.20 5.20 0.02 1.43 4.82

MnTrp2S Nt, OC6A 36.8 0.30 5.24 0.07 1.39 4.94

MnTrp3S O, O� 6A 27.9 0.42 5.11 0.08 1.39 4.86

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contrary to alkaline metal systems in which interaction occurswith the whole p-electron cloud, in the present cases Mn2 + in-teraction is mainly localized at two of the aromatic ring carbonatoms, as observed in the [Cu-Trp]+ moiety.[57] The Mn2 +

cation has a configuration with half-filled 3d orbitals, so to de-crease the Pauli repulsion due to interaction with the ligand,they hybridize with the empty 4s and 4p orbitals. Such a phe-nomenon has been explained for the interaction of Mn2+ withserine and cysteine and was observed in some recent re-ports.[58, 84] For instance, in the MnPhe1S system (assuming theNMnCring plane as xy) the metal cation 3dxy orbital hybridizeswith 4px and to some extent with 4py leading to a decrease inrepulsion of coordination centers and especially that of thebackbone nitrogen group (Figure 3 a). Moreover, for further re-duction of repulsion, a weaker hybridization between dz2 and4pz of Mn2 + occurs. The same type of hybridization also occursin MnTyr1S. Natural population data reported in Table 5 are anindication of the fact that hybridization in MnTrp1S is mainly

of sd type with a small contribution of dp. For the lattersystem, repulsion due to coordination, especially that causedby the donor carbon ring, is reduced by hybridization (Fig-ure 3 b).

The C�C bond lengths of aromatic rings increase upon com-plexation by 0.016, 0.012, and 0.034 � for MnPhe1S, MnTyr1S,and MnTrp1S, respectively. These changes suggest a slight de-crease in the ring aromaticity. For the 2S species, other minimaon the PES for these complexes have been considered due totheir CS-type configuration. The coordination nature of thesemoieties resembles those of glycine complexed with manysingly charged cations, such as Cu+ ,[16, 30] which have been re-ported as the most stable species. Also, the aforementioned2S moiety resembles one of the [Mn-glycine]2 + structures,which was found as the most stable CS form and second moststable isomer on the PES.[58] In terms of type of coordination,the 2S moiety resembles 1S with the only difference beingthat the side-chain aromatic ring is not directly involved in co-ordination with the metal cation. MnPhe2S is different tosome extent from analogous structures of the other two sys-tems such that instead of amino hydrogen, the trans carboxylgroup hydrogen atom is the one that is directed toward thering (Figure 2). In the [Mn-Phe]2 + PES search, no structure simi-lar to MnTyr2S and MnTrp2S was obtained, even if a similar in-itial configuration was used. What can be noticed though inthe 2S structure of all three species is the lack of cation–p in-teraction, which can be explained by considering the highestsingly occupied molecular orbital (SOMO). Figure 3 c displaysthis orbital for MnTyr2S. As can be seen, the major portion ofthis orbital is located on the aromatic ring, which suggeststhat the ring is partially oxidized by Mn2 + , because it hasnearly been singly occupied. The same characteristic has beenobserved for the most stable forms of similar AA complexeswith Cu2 + .[57] Clearly the extent of aromatic AA oxidation byMnII is less than that with CuII. This is associated with a chargedepletion on manganese of 0.36–0.61 (see Table 5) whereas,with Cu2 + , charge reduction is almost equal to one unit andthe copper cation becomes singly charged.[57] The lower abilityof Mn2 + relative to Cu2 + in oxidizing the AA can be attributedto the half-filled 3d5 electronic configuration of Mn2+ and thusto its higher electronic state stability with respect to Cu2+ .Comparison of the manganese charge in 2S structures ofTable 5 reveals that the AA in MnTrp2S is oxidized to a largerextent than in the other two cases. This observation can be at-tributed to better indole ability to delocalize the induced par-tial positive charge. Natural bond orbital (NBO) analysis indi-cates that due to the increase in partial positive charge of theindole ring and thus its larger repulsion with the metal cation,the weak N�H–p interaction in the similar system of MnTyr2Swith an energy of 2 kcal mol�1 becomes even weaker inMnTrp2S with its energy being 0.3 kcal mol�1.

As stated earlier, the distinct difference between 2S and 1Scan be attributed to the absence of p–ring interaction withthe metal cation in the former. It can be suggested, based onthe relative energies of Table 5, that the major reason for theabove differences pertains to p–cation interaction, such thatthe aromatic side-chain interaction contribution to the stabili-Figure 3. SOMOs of MnPhe1S (a), MnTrp1S (b), and MnTyr2S (c) isomers.

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zation of MnPhe1S, MnTyr1S, and MnTrp1S is about 30 kcalmol�1 for the first two and 37 kcal mol�1 for the latter. By com-parison of the interaction site distances of AA with the cation,such as Mn–OC and Mn–Nt, it is realized that such lengths arelarger in 1S relative to 2S moieties. This difference can be ac-counted for by the fact that in 2S complexes, most of themetal’s charge interaction is with Nt and OC sites, thus causingthe electrostatic interaction to be mainly localized with them,which results in stronger interaction and shorter distances.However, in 1S species, the metal charge is partially involvedin p-system interaction, and thus electrostatic interaction withNt and OC is weaker leading to longer Mn–OC and Mn–Nt

lengths. This fact has also been observed in systems with Cu+

–AA interaction.[57] In the MnTrp1S structure, similar toMnPhe1S and MnTyr1S, interaction of the metal cation occurswith the six-membered ring rather than with the five-mem-bered ring in the side chain, which is due to a larger electro-static potential in the six-membered ring[128] and lesser defor-mation of the AA. Higher stability of about 7 kcal mol�1 ofMnTrp1S relative to the other two systems (Table 5) can be ex-plained by the presence of a five-membered ring in thissystem and its effect in stabilizing the cation–indole interac-tion. For instance, NBO analysis suggests a charge transfer forp(C�C)ring–4sMn in MnTrp1S leading to an interaction energyamounting to 15.0 kcal mol�1, whereas the same interaction inMnPhe1S and MnTyr1S gives rise to 10.5 and 9.5 kcal mol�1

stabilization, respectively. The lower distance of Mn–Cring inMnTrp1S compared to the other two systems is another pieceof conforming evidence.

The next structure studied is 3S, which is more stable than2S in all three cases. It is a SB-type species that results fromcarboxylate interaction of zwitterionic AA with the metalcation. An analogous kind of interaction has led to the moststable isomer of the [Mn-glycine]2 + system on the PES.[58] Thehigher stability of 3S relative to 2S in these systems (seeTable 5) is an implication of the fact that interaction of oxygenatoms of the carboxylate end of zwitterionic AA with the man-ganese cation has a more stabilizing effect than the interactionwith backbone Nt and OC of neutral AA. Namely, electrostaticinteraction of the two negatively charged atoms of carboxylateand the positive metal cation is large. However, the aromaticside chain in the 1S structure causes the combination of cationinteraction with Nt and OC of the backbone group and cation–p interaction to have a more stabilizing effect than strong elec-trostatic interaction between two concentrated charges in theSB-type complex.

Theoretical IR spectra along with experimental spectra ob-tained by the IR multiple photon dissociation technique are re-garded as an invaluable aid in determining the most plausiblecomplexes. The 1S structures show a large energy differencefrom all other investigated species in this research, so witha high level of confidence they can be regarded as the mostconceivable species that can be observed experimentally. Thus,theoretical IR study of the most stable isomers of the afore-mentioned three systems provides us with precious informa-tion. Figure S3 illustrates their calculated spectra, which are si-mulated by employing Lorentzian convolution with all vibra-

tional frequencies scaled by a factor 0.96 for future compari-son to experimental data.

Thermochemical Analysis of [Mn-Phe]2 + , [Mn-Tyr]2 + , and[Mn-Trp]2 + Systems

According to the results summarized in Table 6, the order ofAA affinity of Mn2 + (DU0

298) is as follows: Trp>Tyr>Phe. Thestrongest interaction corresponds to Trp due to the side-chainindole group and its interaction with the metal cation. In fact,

the nitrogen atom of indole’s five-membered ring causesa more effective six-membered p-system interaction by desta-bilizing it in Trp relative to the other two cases. The aboveorder of interaction strength corroborates well with Cu+ /2 + in-teraction order,[57] Ag+ ,[45] and also with alkaline metal cationinteraction with same AAs.[71, 94, 97, 99] At the CCSD(T) level oftheory, the Mn2+ affinity for Trp, Tyr, and Phe is 226.3, 213.3,and 210.9 kcal mol�1, respectively. By focusing on bonding en-ergies De resulting from CCSD(T) calculations, and comparingthem with those of B3LYP/basis data for the three systems inTable 6, a difference of about 0.1–1.8 kcal mol�1 can be recog-nized. As in the previous section the level of agreement be-tween these two levels of theory is excellent. The remarkablething is that although the B3LYP method in systems with highelectron delocalization overestimates their energy, somethingthat occurred for the cysteine case (Table 4), it seems that over-estimation of energy by B3LYP is minute in these systems de-spite the high delocalization.

Unfortunately no experimental values exist for comparisonwith the above calculated parameters, so we have to rely onthe comparison of DFT results with those obtained using theaccurate CCSD(T) level of theory.

2.3. Other [Mn-AA]2 + Systems and Absolute Affinity ofMn2 + for the Remaining a-AAs

With regard to previous work on Mn2+ interaction with gly-cine, lysine, and histidine,[58, 84] and taking into account the

Table 6. Mn2+–AA interaction energies [kcal mol�1] in [Mn-phenylala-nine]2 + , [Mn-tyrosine]2 + , and [Mn-tryptophan]2 + .

Phe Tyr TrpInteraction energies Method Mn2+ Mn2 + Mn2 + Cu2 + [e]

De B3LYP[a] 219.5 224.5 238.6B3LYP[b] 211.5 215.6 229.5 �323CCSD(T) 213.3 215.7 228.8

D0[c] 211.6[d] 213.9[d] 226.8[d]

DU0298

[c] 210.9[d] 213.3[d] 226.3[d]

DH0298

[c] 210.9[d] 213.3[d] 226.3[d]

DG0298

[c] 213.2[d] 215.2[d] 228.0[d]

[a] Determined at the B3LYP/6-31G(d,p)//B3LYP/6-31G(d,p) level. [b] Deter-mined at the B3LYP/basis//B3LYP/6-31G(d,p) level. [c] After taking intoconsideration corrections determined at the B3LYP/6-31G(d,p) level.[d] Determined at the CCSD(T)/basis//B3LYP/6-31G(d,p) level. [a] Valuetaken from ref. [57] at the B3LYP level.

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structures studied in Section 2.1 for metal cation interactionwith serine and cysteine, it has been recognized that a sidechain including a donor heteroatom can be a significant stabil-ity factor. This is so because, in the [Mn-AA]2 + complex of CStype, the side-chain heteroatom together with backboneamino nitrogen and carbonyl oxygen are involved in metal co-ordination resulting in the most stable conformer. Such CSmoieties have been reported for interaction of Ser and Cys,[21]

Asp,[19] His[20] with Ca2 + and Ba2+–Asp[19] complexes. For thistype of AA, as an important factor their low influence ofproton affinity[19, 129] has caused the CS form to assume a stablestructure, such as those reported in Na+ ,[18, 19, 71] Li+ , Cs+ ,[19] andAg+ [18] systems. An aromatic side chain has analogous behav-ior, generating cation–p interaction and causing a CS speciesto be the most stable isomer on the [Mn-AA]2+ PES. However,as has been reported for [Mn-glycine]2+ ,[58] and obtained in thefollowing search for complexes without an electron-rich sidechain (e.g. [Mn-Ala]2 + , [Mn-Pro]2+ , [Mn-Leu]2 +) the most stablestructure is a SB. This is caused by interaction of the zwitterion-ic form of AA with cation, whereas the CS species with back-bone amino nitrogen and carbonyl oxygen involved in metalcoordination assumes second order in stability rank. For theseAAs, proton affinity has a significant influence in stabilizationof the zwitterionic form interacting with the metalcation.[19, 130, 131] As evidence, the above effect in the prolinecase has caused the SB to become the most stable structure of[Na-Pro]+ [17] and [Ag-Pro]+ .[45] Thus, electrostatic interaction ofthe negatively charged carboxylate stabilizes the metal cationmore than interaction of neutral AA through Nt and OC ends.In an investigation on interactionof glycine as the simplest AAwith some doubly chargedmetals, such as Ca2 + , Mg2+ , andZn2+ , and singly charged specieswith high dipole polarizability,such as Ca+ and Al+ , the sametrend has been reported.[31] An-other important point worthmentioning is that in SB specieswith high electrostatic interac-tion, the metal high-spin elec-tronic state remains the groundstate after complexation. In addi-tion, the high-spin nature ofcomplexes resulting from doublycharged first-row transition-metal cations, such as Fe2+ , Co2 +

, Ni2 + , and Mn2+ , interactingwith glycine has been report-ed.[34]

Figure 4 depicts the moststable form of the remainingAAs complexed with Mn2 + . BothAsp and Glu choose the CS formas their global minimum struc-ture on interacting with Mn2+ .This finding is at variance with

the Ca2 + and Ba2 + complexes. In the latter two systems, con-trary to Asp, Glu assumes the SB-type structure after beingbound to the alkaline earth cation. This can be explained by ef-fective charge microsolvation in AA interaction with doublycharged transition metals, such as Mn2+ , Ni2 + , Cu2+ , andFe3 + .[34] The above effect is mainly due to the covalent part ofthe interaction,[34] which to some extent controls that causingthe side-chain heteroatom interaction in overcoming the insta-bility due to deformation of Glu AA, thus resulting in the CSform of [Mn-Glu]2 + being the preferred structure. Constructiveagostic interactions between the C�H of the side chain andmetal cation have been observed in CS complexes involvinga long and heteroatom-containing side chain. The [Mn-Arg]2 +

complex of Figure 4 shows such a characteristic. The impor-tance of similar interactions has been mentioned for stabilityof some transition-metal complexes of Cu+ by Yanezet al.[132, 133] Moreover, in the lysine interaction with Mn2 + [84] andCo2+ ,[83] this type of interaction has been reported. It is noticedthat the strength of the agostic interaction in [Mn-Arg]2+ isless than that in [Mn-Lys]2 + . In the former case, two agostic in-teractions through g and d CHs each contribute 2 kcal mol�1 tosystem stability, which is considerably less than the similar re-ported interaction in the [Mn-Lys]2+ system of 7.5 kcal mol�1.[84]

As was stated in previous sections, DU0298 has been taken as

the absolute AA affinity of manganese. The DU0298 values at

the B3LYP and CCSD(T) levels of theory for all 20 natural a-AAsare compiled in Table 7, in which the fourth column shows rel-ative affinities computed at the CCSD(T) level. Notably, findingthe most stable conformers of free AAs is a highly challenging

Figure 4. Most stable structures obtained for optimized geometries of [Mn-amino acid]2+ systems. Distances arein �.

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issue. Stable structures in a 2 kcal mol�1 window were initiallyobtained by a PES search at the semiempirical level followedby B3LYP optimization. Clearly such a procedure becomes im-practical for long-chain AAs, such as Lys, Met, and Arg. In suchcases intuition and the most plausible torsion angles wereused. Finally, our global minima were checked against thosefound experimentally by Alonso et al. ,[123, 124, 134–141] and compu-tationally by Lin et al.[126, 127, 142–146] The global minimum of Argwas taken directly from reference [144] . The smallest Mn2+ af-finity value corresponds to glycine whereas the highest per-tains to arginine. Similar results have been reported for singlycharged species, such as Ag+ ,[45, 64] Cu+ ,[30] and Na+ [18] com-plexes. Among this series, the lowest affinity values are associ-ated with aliphatic AAs whereas the highest values relate toAAs with a side-chain nitrogen atom available for coordinationwith metal cation.

Figure 5 illustrates the correlation between relative AA affini-ties of Ag+ and Na+ reported by Bosque[49] and those obtainedexperimentally for Cu+ ,[59] with the Mn2+ results of the presentstudy. Regression analyses are performed and correlation linesare drawn based on aliphatic AA complexes. Although largedifferences exist in absolute affinities due to the higher chargeof Mn2 + , a similarity in trend of relative affinities is observed.Better resemblance is seen in Figure 5 a and b for the correla-tion with aliphatic AA affinities for Cu+ and Ag+ than in thecase of Figure 5 c for Mn2 + versus Na+ data. This differencecan be most likely attributed to the difference in bondingnature and higher charge transfer in the transition-metal cat-ions relative to that of Na+ . In the case of the remaining AAsof Figure 5, due to side chains with coordination ability, moredisorder is seen relative to the correlation lines. Relatively, allaffinity values except for Cys in correlation with Cu+ and Metwith Ag+ lie above the correlation lines. Such a fact is an indi-cation of a rising trend in affinity with more electron-richgroups present in the side chain. As evident from Table 7, thehistidine affinity of Mn2+ is much higher than that of trypto-phan. A similar trend has also been reported for affinities toNa+ ,[71] Ag+ ,[45, 64] and Cu+ .[30] This is because, in histidine, inter-action does not occur from the p-system side; instead, nitro-gen is directly involved in interaction with the metal cation.This is contrary to what has been reported for Cu2+ , for which

the Trp affinity has been foundto be higher than that of His.[57]

The reason can be assigned tothe lower ionization energy ofTrp and the fact that Trp hasbetter electron delocalizationability than His. A good agree-ment is found among affinityvalues computed at the B3LYPand CCSD(T) levels (Table 7) forserine, threonine, asparagine,tryptophan, glutamine, and argi-nine, with differences as small as0.1–0.7 kcal mol�1. The differen-ces are somewhat larger forother AAs. Relative affinity

values (calculated using CCSD(T) absolute affinities) of AAs inTable 7 cover a range of about 86.0 kcal mol�1. This figure canbe regarded as a good benchmark for comparison of competi-tion among free AAs to bind to the manganese cation inlarger biomolecules.

3. Conclusions

The coordination properties of all 20 AAs to Mn2 + have beenstudied by using first-principles quantum mechanical computa-tions. The complexes of two nonaromatic AAs (Ser and Cys)and three aromatic AAs (Trp, Tyr, and Phe) with Mn2+ havebeen considered in special detail to provide a complete pictureof low-energy isomers and conformers, and to assess theground spin state. The results reveal that the most stable struc-tures are of the CS form in all cases. In [Mn-AA]2 + (AA: Ser andCys) systems, tridentate OOH/OC/Nt and SSH/OC/Nt interactionwith the metal cation, and in [Mn-AAarom]2 + (AAarom: Phe, Tyr,and Trp) cases, tridentate ring/OC/Nt species, in which themetal cation interacts with the side-group p system, havebeen found as the most stable structures. All other AAs thatbear an electron-rich group in their side chain share this CSstructure as the most stable tautomer. This finding is in sharpcontrast with complexes of aliphatic AAs for which the moststable structure is a SB involving metal-cation interaction withthe carboxylate anion of zwitterionic AA.

Accurate bond energies have been obtained at the CCSD(T)level for the most stable structure of all 20 systems. A bindingenergy (De) decrease of approximately 5 kcal mol�1 has beenobtained, by substitution of oxygen in the serine side chainwith sulfur in the cysteine side chain. Bond energies in[Mn-AAarom]2 + (AAarom: Phe, Tyr, and Trp) have been determinedas [Mn-Trp]2 +> [Mn-Tyr]2 +>Mn-Phe]2 + . This order mainly cor-responds to the ability of the AA p system to interact withMn2+ , but it relates to some extent to the ability for delocaliza-tion of partial positive charge that has been developed in theside-chain aromatic ring. Finally, absolute affinities of Mn2 + forall 20 natural a-AAs have been calculated at the accurateCCSD(T) level as well as with the B3LYP density functional. Cor-relations have been drawn between the relative affinities toMn2+ and those to Cu+ , Ag+ , and Na+ . It was found that the

Table 7. Absolute and relative affinities, DU0298, for Mn2 + [kcal mol�1] of the 20 a-AAs, determined at the

B3LYP/basis//B3LYP/6-31G(d,p) level.

Amino acids CCSD(T) B3LYP Relative affinity Amino acids CCSD(T) B3LYP Relative affinity

glycine 165.9 169.7 0.0 methionine 205.9 211.5 40.0alanine 171.8 176.2 6.0 glutamic acid 208.5 210.6 42.6valine 176.4 182.3 10.5 phenylalanine 210.0 208.2 44.1isoleucine 178.2 184.1 12.3 tyrosine 212.4 212.3 46.5leucine 179.7 184.8 13.8 asparagine 216.5 217.8 50.6proline 183.6 188.4 17.8 tryptophan 225.4 226.1 59.5cysteine 187.4 191.2 21.5 glutamine 228.2 229.8 62.4serine 192.5 192.1 26.6 lysine[a] 245.8 246.7 80.0threonine 196.5 197.2 30.6 histidine[a] 249.4 250.8 83.5aspartic acid 202.1 205.0 36.2 arginine 251.9 257.7 86.0

[a] Value taken from ref. [84] after including 0.9 kcal mol�1 for thermal correction to free Mn2 + .

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higher charge of Mn2 + leads to much higher affinities, andthat larger charge transfer to the AA modifies the affinitytrends for AAs with strong electron-donating ability in theirside chain.

Acknowledgements

We would like to acknowledge financial support from the re-search council of Shahid Beheshti University. Also the technical

support of the chemistry computational center at Shahid Behesh-ti University is gratefully acknowledged.

Keywords: ab initio calculations · amino acids · cations ·density functional calculations · manganese

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Figure 5. Comparison of the relative amino acids Mn(II) cation affinities withtheir relative a) Cu(I)59, b) Ag(I) 49, c) Na(I)49 cation affinities. Regression analy-ses were carried out and correlation lines are drawn by employing aliphaticamino acid complexes data (solid circles).

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Received: November 22, 2012Revised: February 13, 2013Published online on && &&, 2013

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ARTICLES

M. H. Khodabandeh, H. Reisi,M. D. Davari, K. Zare, M. Zahedi,*G. Ohanessian*

&& –&&

Interaction Modes and AbsoluteAffinities of a-Amino Acids for Mn2 + :A Comprehensive Picture

The full works: The first completeseries of affinities of a divalent metalion (Mn2 +) for all amino acids calculatedat the B3LYP and CCSD(T) levels oftheory is presented (see figure). Thetrends are compared with those forother cations.

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