Journal of Molecular Structure: THEOCHEM 940 (2010) 95–102

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Journal of Molecular Structure: THEOCHEM

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Interaction of alanine with small water clusters; Ala–(H2O)n (n = 1, 2 and 3):A density functional study

Nidhi Vyas, Animesh K. Ojha *

Department of Physics, Motilal Nehru National Institute of Technology, Allahabad 211004, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 14 July 2009Received in revised form 25 September 2009Accepted 8 October 2009Available online 13 October 2009

Keywords:Alanine–water complexesDFTVibrational stretching modes

0166-1280/$ - see front matter � 2009 Elsevier B.V. Adoi:10.1016/j.theochem.2009.10.015

* Corresponding author.E-mail addresses: animesh_r1776@rediffmail.com

Ojha).

Density functional theory (DFT) calculations for the hydrogen bond interaction between alanine (Ala) andwater clusters Ala–(H2O)n (n = 1, 2 and 3) have been carried at B3LYP/6-31G(d) level of theory. The opti-mized Ala–(H2O)n complexes are solvated in aqueous medium using polarizable continuum model (PCM)to see the effect of bulk water interaction on Ala–(H2O)n complexes. Structural parameters and stabilitiesof the Ala–(H2O)n (n = 1, 2 and 3) conformers have been discussed in terms of relative stable energies. TheAla–(H2O)n complexes, A [Ala + (H2O)], C [Ala + (H2O)2] and E [Ala + (H2O)3], where the water molecule isattached only with –COOH group of Ala molecule, are the most stable conformers in gas phase and aqu-eous medium for n = 1, 2 and 3 clusters. However, the Ala–(H2O)n complexes, where water molecules areattached through both, –COOH and –NH2 groups of Ala are less stable. Thus, the conformers, A, C and Eare the most favorable conformers in gas phase and aqueous medium. The clusters with three watermolecules are dominated by strong hydrogen bond interactions over one and two water molecules.The strength of hydrogen bond interaction in Ala–(H2O)n complexes are increasing on going from gasphase to aqueous medium. All Ala–(H2O)n complexes are shown thermodynamically stable with respectto separate monomers in gas phase and aqueous medium. Potential energy curves are drawn for the con-formers, A, C and E and found that the depth of the potential well increases upon the addition of the watermolecules in Ala–(H2O)n complexes.

� 2009 Elsevier B.V. All rights reserved.

1. Introduction

Hydrogen bond plays important role in many biological andchemical processes. Among the various advantages of hydrogenbonds, the most important one is to get the stabilize structure ofneutral and zwitterionic form of the biological molecules. The for-mation of hydrogen bond is highly sensitive to solvent mediumwhich leads a variety of intermolecular hydrogen bonded com-plexes. The presence of –COOH and NH2 functional groups in bio-logically important molecules makes them favorable forhydrogen bonding in aqueous medium. In hydrogen bond interac-tion between water and biological molecules, the equilibriumshifts towards the water (polar) molecules causing the formationof hydrogen bonds. This can be easily understood by the followingequation:

ðA� XÞ � ðH2OÞ ! Aþd . . . X�d � ðH2OÞnwhere X is an electronegative atom. Hydrogen bond is one of themost common binding mechanisms in the nature.

ll rights reserved.

, animesh@mnnit.ac.in (A.K.

The strength of hydrogen bond ranges from 1 to 40 kcal/mol.Several spectroscopic techniques have been used to study thehydrogen bonded systems. Vibrational spectroscopy is especiallysuited for such a study since the strength of hydrogen bond caneasily be estimated from the vibrational wave number and bondlength. It is well known that amino acids are bifunctional com-pounds having two functional groups, –COOH and –NH2 [1–4]. Ingas phase, the more stable structure of any amino acids is NH2–CHR–COOH, which is a neutral form. This is also a predominantform when they are solvated in nonpolar solvents. However, in po-lar solvent they exist mostly in zwitterionic form. The determina-tion of the conformational details of the biological macromoleculesis important to understand their functions in biological and chem-ical processes. A number of spectroscopic studies [5–9] have beendone to get the signature of hydrogen bridging mode in thespectrum and also to explore the effect of hydrogen bonding onstructure and properties of biological molecules. The vibrationalwavenumber of the hydrogen bond bridging mode owing to thefact that the IR and Raman intensities of these modes are too lowand the position is expected to be �100 cm�1 which is not easilyaccessible experimentally in an easy manner. Due to this the theo-retical studies are used to calculate the wavenumber and intensi-ties and of the hydrogen bond bridging mode and also to identify

96 N. Vyas, A.K. Ojha / Journal of Molecular Structure: THEOCHEM 940 (2010) 95–102

and interpret the wavenumber and intensities of unassigned vibra-tional modes. However, since it is difficult to implement thisapproach directly for large systems such as proteins, which maytake larger calculation time, a model system has to be studied firstto understand the properties of amino acids.

Alanine (Ala) is the smallest naturally occurring chiral aminoacid. To understand the conformational properties of peptidesand proteins, Ala is most suited model molecule. In many studies[10–12], the amino acid has been treated in the neutral form. Sol-vent plays a crucial role in energetic, conformational and spectro-scopic properties of molecules, altering the mechanism of chemicalreactions. These studies have provided important information onthe intermolecular interactions that take place in the active siteof enzymes and on the process of self-organization. The Ala mole-cule may interact with water molecules via –COOH and –NH2

functional groups and leading to the different hydrogen bondedAla–(H2O)n (n = 1, 2 and 3) structures. The direct interaction ofAla molecule with water cluster (n = 1, 2 and 3) through hydrogenbond falls under the course of specific interaction, which is not arealistic approach to model the reference system embedded inaqueous medium. Therefore, to account the bulk aqueous effect,the Ala molecule is solvated in aqueous medium at B3LYP/6-31G(d) level of theory using polarizable continuum model (PCM).In PCM solvation model, the reference molecule is kept in a spher-ical cavity and the cavity is placed in solvent medium where thesolvent medium effect is theoretically characterized by the dielec-tric constant of the solvent medium.

The goal of the present study is to investigate the interaction ofAla with one, two and three water molecules, Ala–(H2O)n (n = 1, 2and 3) focusing on the structural parameters and energies aspectsof the different Ala–(H2O)n hydrogen bonded complexes. Thegeometries of Ala–(H2O)n complexes are optimized in two ways;(i) keeping the water molecules near to –COOH functional groupof Ala such that the water molecules form hydrogen bonds with–COOH group only and (ii) the water molecules are kept in sucha way that they form hydrogen bonds with both, –COOH and –NH2 groups of the Ala molecule. These arrangements may givemore insight to understand the role of different functional groupsin predicting the more stable Ala–(H2O)n hydrogen bonded com-plexes in gas phase and aqueous medium. To see the bulk water ef-fect on structural parameters and energy of Ala–(H2O)n complexes,the gas phase optimized geometries of Ala–(H2O)n complexes aresolvated in aqueous medium. The potential energy curves are cal-culated for the hydrogen bond bridging mode in Ala–(H2O), Ala–(H2O)2 and Ala–(H2O)3, complexes. The variation of BE per watermolecule is also investigated for hydrogen bonded complexes inboth, gas phase and aqueous medium. Thus the present study isexpected to give a detailed overview of the nature of hydrogenbond interaction of Ala with small water clusters in gas phaseand aqueous medium.

2. Theoretical method

Recently, density functional theory (DFT) has been accepted byquantum chemistry community as a cost effective approach for thecomputation of molecular structures, vibrational frequencies andenergies of chemical reactions. Many studies have shown thatmolecular structures calculated by DFT methods are more reliablethan MP2 methods [13–15]. While there is sufficient evidence thatDFT provides an accurate description of the electronic and struc-tural properties of solids, interfaces and small molecules, relativelylittle is known about the systematic performance of DFT applica-tions to molecular associates. To further access the reliability ofDFT methods in understanding the theory of molecular associationmainly through hydrogen bonds, all the calculations in the presentstudy have been carried out employing DFT method at B3LYP level

of theory. The optimized geometries for both, isolated and Ala–(H2O)n (n = 1, 2 and 3) hydrogen bonded complexes were calcu-lated using DFT with Becke’s three parameter functional [16–18]and non-local correlation provided by Lee, Yang and Parr (B3LYP)[19] using GAUSSIAN 03 simulation package. All the calculationswere carried out with a small basis set, 6-31G(d). To account thebulk aqueous medium effect, the optimized geometries of Ala–(H2O)n (n = 1, 2 and 3) complexes were solvated in aqueous med-ium via the integral equation formalism polarizable continuummodel (IEFPCM) that is the default PCM formulation in GAUSSIAN03 [20]. The PCM [21–23] creates a realistic molecule-shapedcavity within the solvent continuum from interlocking spherescentered on atoms or functional groups within the solute molecule.The radii for the spheres were those of the united atom topologicalmodel [22]. The reaction field in the solvent due to the solutecharge distribution is represented as an apparent charge on thesurface of the cavity. The surface charge distribution is calculatedfrom the electrostatic potential, which has contributions fromboth, the solute charge distribution and the apparent surfacecharge and is solved for iteratively. The dipole moment of thesolute molecule induces a dipole in the solvent molecule and theelectric field applied to the solute molecule by the dipole ofthe solvent molecule interacts with the dipole of the solutemolecule.

The initial geometries for Ala–(H2O)n (n = 1, 2 and 3) hydrogenbonded complexes were constructed in two ways (i) the watermolecules form the hydrogen bond only with –COOH functionalgroup of Ala and (ii) the water molecules form the hydrogen bondswith both the functional groups, –COOH and NH2. The optimizedgeometries of Ala–(H2O)n (n = 1, 2 and 3) complexes calculated attheir minimum energy configuration are presented in Fig. 1.Fig. 1(A), (C) and (E) represents the optimized structures of Ala–(H2O)n (n = 1, 2 and 3) complexes as considered in case (i) andFig. 1(B), (D) and (F) represents optimized structures as discussedin case (ii). In case (i), the initial geometry was given in such away that the –COOH group of Ala directly faced towards the elec-tron lone pair of H2O expecting to form hydrogen bonds. Severalstable conformers of Ala–(H2O)n complexes exist for n = 1, 2 and3 with various hydrogen bond interaction depending on thechoices of the lone pairs on water and O or the N atom of Ala forforming the hydrogen bonds. Only those stable geometries ofAla–(H2O)n (n = 1, 2 and 3) complexes have been reported in thepresented study which have minimum energy configurationamong all possible configurations and their final structure nicelymatches with our assumptions (i) and (ii). The length of the hydro-gen bonds is analyzed to explain the strength of the hydrogenbonds. The binding energy (BE) of the Ala–(H2O)n (n = 1, 2 and 3)hydrogen bonded complexes is calculated using the followingrelationship:

BE ¼ ½EAB � ðEA þ EBÞ�;

where AB stands for the complex and A and B stand for each of thetwo monomer molecules. The effects of basis set superposition error(BSSE) in Ala–(H2O)n (n = 1, 2 and 3) complexes were also taken inconsideration using counterpoise method to obtain the correctedBE, DCP

e [5].

3. Results and discussion

The optimized geometries of Ala–(H2O)n (n = 1, 2 and 3) hydro-gen bonded complexes calculated in gas phase at B3LYP/6-31G(d)level of theory are presented in Fig. 1(A, B, C, D, E and F). The opti-mized ground state energies, relative energies of conformers B, Dand F with respect to its other conformers, A, C and E and dipolemoment of Ala–(H2O)n (n = 1, 2 and 3) hydrogen bonded complexes

Fig. 1. Optimized ground state geometries of Ala–(H2O)n (n = 1, 2 and 3) complexes calculated at B3LYP/6-31G(d) level of theory.

Table 1The energies and dipole moments of Ala–(H2O)n (n = 1, 2 and 3) complexes calculated at B3LYP/6-31G(d) level of theory in gas phase and aqueous medium.

Complexes Gas phase Aqueous mediumB3LYP/6-31G(d) B3LYP + PCM/6-31G(d)

Energy (hartree) Relative energy (kcal/mol) Dipole moment (D) Energy (hartree) Relative energy (kcal/mol) Dipole moment (D)

(A) Ala + (H2O) �400.17060 0 0.594 �400.18922 0 1.331(B) Ala + (H2O) �400.15672 8.7 3.441 �400.18535 2.4 4.784

(C) Ala + (H2O)2 �476.60539 0 4.466 �476.62999 0 5.720(D) Ala + (H2O)2 �476.59232 8.2 4.032 �476.62024 6.1 6.547

(E) Ala + (H2O)3 �553.03277 0 3.048 �553.05880 0 2.684(F) Ala + (H2O)3 �553.00998 14.3 2.868 �553.04669 7.5 4.200

N. Vyas, A.K. Ojha / Journal of Molecular Structure: THEOCHEM 940 (2010) 95–102 97

calculated in gas phase and aqueous medium are given in Table 1.The hydrogen bonded complexes of Ala–(H2O)n (n = 1, 2 and 3)presented in Fig. 1(A), (C) and (E), the water molecules were keptcloser to –COOH functional group of Ala molecule as initial guessfor getting the optimized minimum energy configurations ofAla–(H2O)n. The final optimized structure of Ala–(H2O)n complexesappeared to be same as it was given in the initial guess where thewater molecules form the hydrogen bonds with –COOH functionalgroup. The length of hydrogen bond bridging mode, charge on N, Oand H atoms involved in the hydrogen bonding for Ala–(H2O)n

complexes calculated in gas phase and aqueous medium are givenin Table 2. The Ala–(H2O)n (n = 1, 2 and 3) complexes presented inFig. 1B, D and F, the water molecules were kept near to both thegroups, –NH2 and –COOH of Ala molecule as the initial guess forthe geometry optimization and the final hydrogen bonded struc-tures of Ala–(H2O)n (n = 1, 2 and 3) obtained through calculationhave the association of water molecules with –NH2 and –COOH

groups of Ala. The bond length of hydrogen bridging mode chargeson the atoms involved in the hydrogen bonds for Ala–(H2O)n (n = 1,2 and 3) complexes calculated in gas phase and aqueous mediumare given in Table 2. The BE (De), zero point corrected bindingenergy (D0), counterpoise corrected binding energy DCP

e and rela-tive enthalpies (DH) of Ala–(H2O)n complexes were calculated withrespect to the separate Ala molecule in gas phase and aqueousmedium and the values are presented in Table 3. For a given com-plex, the binding energy (De) was determined as a difference be-tween the total energy of the complex and sum of the totalenergies of the isolated monomers (Ala and H2O) contained inthe complex. The relative enthalpies, DH, were calculated at1 bar and 298.3 K with respect to the separate molecules (Alaand H2O). It is interesting to note that the values of De, D0, DCP

e

and DH are decreasing significantly for all possible Ala–(H2O)n

(n = 1, 2 and 3) complexes in going from gas phase to aqueousmedium. The decrease in the values of D0 and DH are more pro-

Table 2Optimized parameters of Ala–(H2O)n (n = 1, 2 and 3) complexes calculated at B3LYP/6-31G(d) level of theory in gas phase and aqueous medium.

Complexes Selected optimized parameters (Å) Charges (e)

Bond (H–O) Bond length(gas phase) (Å)

Bond length(aqueous medium) (Å)

Atoms Charges(gas phase) (e)

Charges (aqueousmedium) (e)

(A) Ala + (H2O) H6–O14 1.73 1.66 O14 �0.79 �0.81H15–O14 0.97 0.98 H16 0.43 0.45H16–O14 0.98 0.98 O3 �0.51 �0.55H16–O3 1.92 2.87 H6 0.44 0.45

(B) Ala + (H2O) H15–O2 2.05 2.02 O2 �0.59 �0.60H15–O14 0.97 0.98 H15 0.41 0.42H16–O14 0.97 0.98 H16 0.39 0.43

(C) Ala + (H2O)2 H6–O14 1.63 1.60 O14 �0.85 0.85H15–O17 1.72 1.72 H15 0.44 0.43H19–O3 1.80 1.83 O17 �0.82 �0.85H15–O14 0.99 0.99 H19 0.44 0.42H19–O17 0.98 0.99 O3 �0.52 �0.54

(D) Ala + (H2O)2 H16–O3 2.13 2.00 O3 �0.47 �0.51H16–O14 0.97 0.98 H16 0.41 0.41H15–O14 0.98 0.99 O14 �0.83 �0.85H15–O17 1.91 1.87 H15 0.41 0.40H19–O17 0.98 0.99 O17 �0.81 �0.86N9–H19 1.92 1.85 H19 0.42 0.43H11–O14 1.99 1.81 N9 �0.78 �0.78

(E) Ala + (H2O)3 H6–O14 1.71 1.58 H6 0.45 0.45H16–O14 1.00 1.00 O14 �0.83 �0.86H16–O17 1.67 1.69 H16 0.43 0.43H19–O17 0.98 0.99 O17 �0.82 �0.85H19–O21 1.84 1.72 H19 0.42 0.43H22–O21 0.98 0.99 O21 �0.81 �0.85H22–O3 2.01 1.82 H22 0.42 0.43

O3 �0.53 �0.53

(F) Ala + (H2O)3 H15–O2 2.05 2.01 O2 �0.57 �0.59H10–O17 2.02 2.09 H15 0.41 0.42H22–O19 1.79 1.78 H10 0.34 0.32H20–O3 1.87 1.86 O17 �0.81 �0.86H20–O19 0.98 0.98 H22 0.42 0.42H22–O17 0.98 0.99 O19 �0.81 �0.84H15–O14 0.97 0.98 O3 �0.49 �0.51

H20 0.44 0.44

Table 3Binding energies De, ZPE-corrected binding energies D0, counterpoise corrected binding energy DCP

e and relative enthalpies DH (all in kcal/mol) of Ala–(H2O)n (n = 1, 2 and 3)calculated at B3LYP/6-31G(d) level of theory in gas phase and aqueous medium.

Complexes Gas phase Aqueous mediumB3LYP/6-31G(d) B3LYP + PCM/6-31G(d)

De (kcal/mol) D0 (kcal/mol) DCPe (kcal/mol) DH (kcal/mol) De (kcal/mol) D0 (kcal/mol) DH (kcal/mol)

(A) Ala + (H2O) 16.1 13.3 12.0 �13.4 7.9 5.5 �5.0(B) Ala + (H2O) 7.4 5.8 2.5 �3.6 5.5 3.6 �0.68

(C) Ala + (H2O)2 33.3 28.1 24.5 �26.0 21.3 15.4 �12.4(D) Ala + (H2O)2 25.1 19.3 17.6 �20.0 15.2 9.0 �9.4

(E) Ala + (H2O)3 45.8 37.5 32.7 �37.1 27.1 18.8 �8.8(F) Ala + (H2O)3 31.5 24.9 21.0 �22.9 19.5 12.3 �9.6

98 N. Vyas, A.K. Ojha / Journal of Molecular Structure: THEOCHEM 940 (2010) 95–102

nounced for complex, E compared to other complexes. Thus thecomplex, E is highly affected both, energetically as well as thermo-dynamically among all possible Ala–(H2O)n complexes in goingfrom gas to aqueous medium. Thermodynamically and energeti-cally, the conformer E is most favorable structure for, Ala–(H2O)n

complexes. Thermodynamically and energetically, the order ofpossible hydrogen bonded complexes of Ala–(H2O)n is E, C and A,respectively. In conformer, A, water molecule forms two hydrogenbonds, H6. . .O14 and H16. . .O3 of length, 1.75 and 1.92 Å, respec-tively. The water molecule in conformer, B forms only one hydro-gen bond, H15. . .O2 of length, 2.05 Å. Both the conformers, C andD have three hydrogen bonds, H6. . .O14 (1.63 Å), H15. . .O17

(1.72 Å) and H19. . .O3 (1.80 Å) and H16. . .O3 (2.13 Å), H15. . .O17

(1.91 Å) and H19. . .O12 (1.92 Å), respectively, between Ala and

water molecules. However, in conformers, D and E the water mol-ecules form four hydrogen bonds, H6. . .O14 (1.71 Å), H16. . .O17

(1.67 Å), H19. . .O21 (2.01 Å) H22. . .O3 (1.84 Å) and H15. . .O2

(2.05 Å), H20. . .O3 (1.87 Å), H22. . .O19 (1.79 Å), H10. . .O17 (2.02 Å),respectively. The potential energy barrier for hydrogen bond bridg-ing mode H. . .O–H for conformers, A, C and E also have calculatedcorresponding to the hydrogen bond bridging mode H6. . .O14

(1.73 Å), H6. . .O14 (1.63 Å) and H6. . .O14 (1.71 Å), respectively.

3.1. Alanine with one water molecule

Two conformers, A and B of Ala–(H2O) were optimized atB3LYP/6-31G(d) level of theory in gas phase and aqueous med-ium and the ground state geometries were shown in Fig. 1.

N. Vyas, A.K. Ojha / Journal of Molecular Structure: THEOCHEM 940 (2010) 95–102 99

The gas phase ground state optimization energy of conformers, Aand B is �400.17060 and �400.15672 hartree, respectively. Therelative gas phase ground state energy of conformer, B with re-spect to A, is 8.7 kcal/mol. The ground state optimization energyof conformers, A and B in aqueous medium is �400.18922 and�400.18535 hartree, respectively. The relative energy of con-former, B with respect to conformers, A, in aqueous medium is2.4 kcal/mol. Therefore, in the aqueous medium the relative en-ergy of conformer, B is decreased by 6.3 kcal/mol compared tothat obtained in gas phase. The dipole moments of both the con-formers, A and B are increasing on going from gas phase toaqueous medium. In conformer, A both, Ala and water moleculesact as proton donor as well as proton acceptor. However, the Alamolecule acts as a proton acceptor and water molecule as protondonor for conformer, B. In conformer A, water molecule formstwo hydrogen bonds (i) the –O atom of water molecule is at-tached through the –H atom of –COOH group (proton donor)of Ala and (ii) the –H atom of water molecule attaches with –O atom of –COOH group of Ala molecule, which act as a protonacceptor. The hydrogen bond distance H6. . .O14, where –COOHgroup acts as proton donor is 1.73 Å which is shorter than thehydrogen bond, H16. . .O3 of length 1.92 Å, where –COOH actsas a proton acceptor. Thus, the hydrogen bond is stronger in casewhere –COOH group is involved as proton donor for the forma-tion of hydrogen bond with water molecule. The hydrogen bondis weaker when –COOH group is associated with water moleculethrough hydrogen bond as a proton acceptor. A similar kind oftrend was observed for the strength of the hydrogen bonds inthe aqueous medium. From Table 2, the length of hydrogen bond(H6. . .O14) of conformer, A is 1.73 Å in gas phase and the bondlength reduces to 1.66 Å in aqueous medium. The reason ofdecreasing the bond length on going from gas phase to aqueousmedium is the increase in the strength of electrostatic interac-tion between the solute and solvent molecules due to the trans-fer of electronic charge on H and O atoms. The charge on atoms,O14 and H6 in gas phase are �0.79e and 0.44e, respectively, andin aqueous medium it increases to �0.81e and 0.45e, respec-tively. The shortening of hydrogen bond causes lengthening incovalent bonds O14–H15 involved in hydrogen bonding. A similarkind of trend regarding the length of hydrogen bonds, charge onO and H atoms and the length of covalent bonds has been ob-served for conformer, B on going from gas phase aqueous med-ium. The conformer B has higher ground state energy by 8.7 and2.4 kcal/mol in gas phase and aqueous medium, respectively,than the conformer A. In conformer, B, the hydrogen bond lengthH15. . .O2 decreases by 0.03 Å in aqueous medium from its gasphase value. As shown in Table 3, the BE, De of conformers Aand B in gas phase (aqueous medium) is 16.1 (7.9) kcal/moland 7.4 (5.5) kcal/mol, respectively, and the value of zero energycorrected BE, D0 is 13.3 (5.5) and 5.8 (3.6) kcal/mol. The value ofDCP

e for conformers, A and B is 12.0 and 2.5 kcal/mol, respec-tively. The values of De and D0 for both the conformer aredecreasing on going from gas phase to aqueous medium. Thelarge value of BE for conformer, A is indicative of strong hydro-gen bonding between Ala and water molecules. On the otherhand, in conformer B, less value of D0 shows a weaker hydrogenbonding between Ala and water molecules. Thus, the orientationof water molecules around the Ala molecules plays an importantrole to decide the strength of hydrogen bonds. The relativeenthalpies of conformers, A and B in gas phase (aqueous med-ium) are �13.4 (�5.0) and �3.6 (�0.68) kcal/mol, respectively.The negative value of enthalpies for conformers, A and B showthe hydration of Ala by one water molecule is exothermic in nat-ure. The larger value of D0 and DH for conformer, A suggestingthat the conformer A is more stable with respect to the dissoci-ation into separate Ala and water molecules in the gas phase.

3.2. Alanine with two water molecules

Two possible conformers of Ala–(H2O)2 complexes, C and Doptimized at B3LYP/6-31G(d) level of theory are presented inFig. 1 at their minimum ground state energy. These two equilib-rium structures of Ala–(H2O)2, C and D, shown in Fig. 1, were opti-mized in both gas phase as well as aqueous medium. In conformer,C, both the water molecules are oriented in such a way that the onewater molecules form hydrogen bond as a proton acceptor andother water molecule form hydrogen bond as a proton donor with–COOH group of Ala molecule. In this configuration, the one watermolecule is oriented in such a way that it forms a hydrogen bondwith the other water molecule. In the conformer C, one water mol-ecule attaches through –H atom of the –COOH group, which is pro-ton acceptor and the second water molecule attaches through the –H atom of first water molecule, which acts as a proton acceptor,and –O atom of –COOH group for which it acts as proton donorfor the –COOH group of Ala. Thus, three hydrogen bonds are pres-ent in Ala–(H2O)2 complex which form a closed loop hydrogenbonded structure. In conformer (D), one water molecule attachesthrough the –O atom of the –COOH and acts as a proton donorand the second water molecule attaches through the –N atom ofthe –NH2 group which act as a proton acceptor. Both the watermolecules are also associated with hydrogen bonds where the sec-ond water molecule is acting as a proton acceptor for the firstwater molecule. In conformer D, the hydrogen bond lengths,H11. . .O14, H19. . .N9, H16. . .O3 and H15. . .O17 in gas phase are 1.99,1.92, 2.13 and 1.91 Å, respectively, and when the complex is sol-vated in aqueous medium these bond lengths decreased to 1.81,1.85, 2.00 and 1.87 Å, respectively. For conformer C, the hydrogenbond lengths H6. . .O14 and H15. . .O17 in gas phase are 1.63 and1.72 Å, respectively, and it decreased to 1.60 and 1.72 Å, in aqueousmedium. The decrease in length of hydrogen bonds for both thecomplexes, C and D in going from gas to aqueous medium is indic-ative of strong electrostatic interactions. The charges on O14 andO17 atoms of water molecules in conformer C are �0.85e and�0.82e, respectively, in gas phase and almost no change in themagnitude of charge was observed upon going from gas to aqueousmedium. However, in conformer, D, an increase of 0.05e was ob-served on O17 in going from gas to aqueous medium and no anychange was noticed in charge on O14. The bond length of O–H cova-lent bond, which involved in hydrogen bond formation, increasesfor both the conformers, C and D. Thus, the hydrogen bond ofAla–(H2O) unit is strengthened while the –O–H covalent bondlength of water is weakened. The binding energy, De of conformersC and D in gas phase (aqueous medium) is 33.3 (21.3) kcal/mol and25.1 (15.2) kcal/mol, respectively, and the value of zero correctedenergy, D0 is 28.1 (15.4) and 19.3 (9.0) kcal/mol. The value of DCP

e

for conformers, C and D is 24.5 and 17.6 kcal/mol, respectively.The values of De and D0 for both the conformer are decreasing ongoing from gas phase to aqueous medium. Due to the large bindingenergy of conformer, C, it dominates in the solution than that ofconformer, B. The less values of De and D0 show weaker hydrogenbonding between Ala and water molecules. The relative enthalpiesof conformers, C and D in gas phase (aqueous medium) are �26.0(�12.4) and �20.0 (�9.4) kcal/mol, respectively. The negative va-lue of enthalpies for conformers, C and D show the hydration ofAla by both the water molecules is exothermic in nature. The largervalue of De and DH for conformer, C suggesting that the conformerC is more stable with respect to the dissociation into separate Alaand water molecules in the gas phase.

3.3. Alanine with three water molecules

Two hydrogen bonded conformers, E and F of neutral Ala withthree water molecules were optimized at their minimum energy

1 2 3

6

8

10

12

14

16

18

20Gas phase

B+D+F

A+C+E

Ala-(H2O)n

B.E

./ H 2O

(Kca

l/mol

)

321

2

4

6

8

10

12

B.E

. / H

2O (K

cal/m

ol)

Water medium

B+D+F

A+C+E

Ala-(H2O)n

a

b

Fig. 2. BE per water molecule for the Ala–(H2O)n (n = 1, 2 and 3) (a) gas phase (b)aqueous medium.

100 N. Vyas, A.K. Ojha / Journal of Molecular Structure: THEOCHEM 940 (2010) 95–102

configuration and shown in Fig. 1E and F. The ground state energiesof conformers E and F are �553.032767 and �553.00998 hartree,respectively, in gas phase and �553.05880 and �553.04669 har-tree, respectively, in aqueous medium. In the conformer E, twowater molecules are attaching directly with –COOH group of Alamolecule through hydrogen bonds and one water molecule isbridging between two water molecules. The first water moleculeacts as a proton acceptor for Ala and the second water moleculeacts as a proton acceptor for the first water molecule and also actsas a proton donor for the third water molecule and the third watermolecule act as a proton donor for –COOH group of Ala. Thus itforms a closed loop hydrogen bonded structures by forming fourhydrogen bonds in conformer, E. However, the structure is openin case of conformer, F where two water molecules are attachedtrough –COOH group and one water molecule is attached through–NH2 group. The conformer, F also has four hydrogen bonds. Forconformer, E, the bond lengths of four hydrogen bonds, H6. . .O14,H16. . .O17, H19. . .O21 and H22. . .O3 are 1.65, 1.67, 1.84 and 2.01 Å,respectively, in gas phase and it reduces to 1.58, 1.69, 1.72 and1.82 Å, respectively, upon introducing the aqueous medium as sol-vent. In conformer, F, the length of hydrogen bonds, H15. . .O2,H10. . .O17, H22. . .O19 and H20. . .O3 are 2.05, 2.02, 1.79 and 1.87 Å,respectively, in gas phase and these hydrogen bond lengths are de-creased to 2.01, 2.09, 1.78 and 1.86 Å, respectively, in aqueousmedium. The strength of hydrogen bond formed only with –COOHgroup in conformer, E is more than that of conformer, F wherehydrogen bonds formed with both, –COOH and –NH2 group ofAla molecule. Thus, the conformer, E likely to dominates in both,gas as well as aqueous medium than the conformer, F. The valuesof De, and D0 for conformer, E are 45.8 and 37.5 kcal/mol, respec-tively, in gas phase and 27.1 and 18.8 kcal/mol, respectively, inaqueous medium. The gas phase value of De is 18.7 kcal/mol higherthan its value in aqueous medium. The values of De, and D0 for con-former, F are 31.5 and 24.9 kcal/mol, respectively, in gas phase and19.5 and 12.3 kcal/mol, respectively, in aqueous medium. The va-lue of DCP

e for conformers, E and F is 32.7 and 21 kcal/mol, respec-tively. For conformer, F also the gas phase value of D0 is higher thanits value in aqueous medium. In conformer, F, the charges on theO2, O17 and O19 are increased by �0.02e, �0.05e and �0.03e,respectively, on going from gas phase to aqueous medium. The rel-ative enthalpies of conformers, E and F in gas phase (aqueous med-ium) are �37.1 (�8.8) and �22.9 (�9.6) kcal/mol, respectively. Thenegative value of enthalpies for conformers, E and F also show thehydration of Ala by both the water molecules is exothermic in nat-ure. The larger value of De and DH for conformer, E suggesting thatthe conformer E is more stable with respect to the dissociation intoseparate Ala and water molecule in gas phase.

4. Binding energy per water molecule for Ala–(H2O)n complexes

The binding energy per water molecule for Ala–(H2O)n com-plexes is defined as follows:

BE=n ¼ ½EAB � ðEA þ EBÞ�=n

where AB stands for the complex and A and B stand for each of thetwo monomer molecules. The values of n are 1, 2 and 3 for Ala–(H2O), Ala–(H2O)2 and Ala–(H2O)3, complexes, respectively.Fig. 2(a) shows the dependence of the BE for Ala–(H2O)n complexesper water molecule for the conformers, A, B, C, D, E and F in gasphase and Fig. 2(b) shows the dependence of BE per water moleculein aqueous medium. It is quite evident from Fig. 2(a) and (b) thatthe BE of Ala–(H2O)n complexes per water molecule increases forthe cluster size n = 2 and decreases on further increase of clustersize, n = 3. The difference in BE per water molecule of conformers,A and B in gas phase is larger compared to difference in aqueous

medium. It is interesting to note that the difference of BE per watermolecule between the conformers, A and B, C and D, E and F are al-most same in the aqueous medium. This indicates that the effect ofbulk water interaction is same for all Ala–(H2O)n conformers. Thevalues of BE per water molecule is larger for the conformers, A, Cand E in both, gas phase and aqueous medium than that of the con-formers, D, E and F. Thus, the conformers, A, C and E in which thewater molecules are attached only through the –COOH group ofneutral Ala are the most stable complexes of Ala–(H2O), Ala–(H2O)2 and Ala–(H2O)3, respectively.

5. Calculation of potential energy curves for Ala–(H2O)n

complexes

The stretching vibration in hydrogen bond complex is qualita-tively similar to that in Van der Waals complex. The potential func-tion of stretching vibration for hydrogen bond bridging mode –H. . .O–H formed between –COOH group of Ala and water mole-cules resembles that of Van der Waals complex except for the factthat the depth of the potential well is much deeper in the case ofhydrogen bonded complex [24]. The standard form of the potential

N. Vyas, A.K. Ojha / Journal of Molecular Structure: THEOCHEM 940 (2010) 95–102 101

function for the stretching vibration of the hydrogen bond may betaken as:

VðRÞ ¼ 4�½ðR0=RÞ12 � ðR0=RÞ6�

where � is the depth of the potential well and R0 is the bond dis-tance at m = 0 vibration level of same potential [24]. R0 is relatedto Re by the equation Re = 21/6R0, where Re is the equilibrium lengthof hydrogen bond, which is essentially the bond distance when the

Fig. 3. Potential energy curves for the –H. . .O–H stretching modes of vibration forthe conformers, A, C and E in gas phase.

molecules involved in hydrogen bonding experience maximumattraction. The concept of potential function discussed above canbe conveniently applied to three more stable structures of Ala–(H2O)n complexes presented in Fig. 1(A), (C) and (E), where thebinding partners are attached with –H atom of the –COOH group.In the case of Ala–(H2O) complex, the hydrogen bond length1.73 Å correspond to –H. . .O–H bond of –COOH group with BE16.1 kcal/mol. An amount of energy equal to binding energy isneeded to dissociate the complex. Then the BE can be taken nearlyequal to the dissociation energy, which is nothing but the depth ofthe potential well. The potential energy varies with R giving a min-imum at equilibrium bond length Re. The potential energy functionsthus calculated for complexes Ala–(H2O)n (n = 1, 2 and 3) are shownin Fig 3(a)–(c). As shown in the graph, the stepwise addition ofwater molecules into the system are found to increase the relativestabilities of the Ala–(H2O)n (n = 1, 2 and 3) complexes. InFig. 3(b) the hydrogen bond distance is 1.63 Å correspond to –H. . .O–H mode of –COOH group of Ala. As the hydrogen bond lengthbecomes stronger, the binding energy is increased hence the depthof the potential well also become deeper. Similarly, in Fig. 3(c) thehydrogen bond length is 1.71 Å and the binding energy is45.8 kcal/mol. Thus, there is a further increase in the depth of thepotential well. Thus the depth of the potential well increases withincrease in strength and BE of the Ala–(H2O)n complexes.

6. Conclusions

The structures of Ala and water molecules are explored by DFTcalculations of equilibrium geometries and molecular energies ofthe Ala–(H2O)n (n = 1, 2 and 3) clusters in two ways (i) the watermolecules were kept near to the –COOH group of Ala moleculesuch that they form hydrogen bond with –COOH group only and(ii) the water molecules were kept in such a way that they formhydrogen bonds with both, –COOH and –NH2 groups of Ala mole-cule. The hydrogen bonded conformers, A, C and E of Ala–(H2O)n

(n = 1, 2 and 3) where water molecules are associated with –COOHgroup of Ala molecule are most stable conformers for n = 1, 2 and 3in gas phase and aqueous medium. Thus, the conformers wherewater molecules are interacting with –COOH group only will bedominating in the gas phase and aqueous medium. The stepwiseaddition of water molecule in the Ala–(H2O)n complexes increasesthe BE of the conformers. The orientation of water molecules playsan important role in deciding the most stable Ala–(H2O)n com-plexes. The strength of hydrogen bond interaction is relativelystronger in aqueous medium than that of gas phase. The bindingenergy per water molecule for Ala–(H2O)n complexes was also dis-cussed. The potential energy curves were drawn for the most sta-ble conformers, A, C and E of Ala–(H2O)n complexes. The depth ofthe potential well increases upon the addition of the water mole-cules in Ala–(H2O)n complexes.

Acknowledgements

N.V. is thankful to MNNIT, Allahabad for granting the researchfellowship. A.K.O. is thankful to RKS for providing the access ofGAUSSIAN 03 for performing the DFT calculations.

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