Structural Stability in Dimer and Tetramer Clusters of L-alanine in the

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B: Biophysics; Physical Chemistry of Biological Systems and Biomolecules

Structural Stability in Dimer and Tetramer Clusters of L-alanine in the Gas-phase and the Feasibility of Peptide Bond Formation E J Padma Malar, and Divya Palani J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b01629 • Publication Date (Web): 30 May 2018 Downloaded from http://pubs.acs.org on May 30, 2018

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The Journal of Physical Chemistry

Structural Stability in Dimer and Tetramer Clusters of L-alanine in the Gas-phase and the Feasibility of Peptide Bond Formation E. J. Padma Malar* and P. Divya National Centre for Ultrafast Processes, University of Madras, Taramani Campus, Chennai600113, India. Email:[email protected]

Abstract Stability in low-energy structures of the dimer and tetramer clusters of L-alanine in gas-phase is studied by accurate quantum chemical computations at DLPNO2013-CCSD(T) level. It is found that the dispersion interaction energies in the dimer (-0.3 to -0.6 kcal/mol) and in the tetramer (-1.3 to -2.5 kcal/mol) have small role in the stability of the clusters as compared to the hydrogen bond energies -4.1 to -14.2 and -32.2 to -40.1 kcal/mol, respectively. The hydrogen bond energy in the alanine cluster is obtained from the DLPNO2013CCSD(T)//B2PLYP/def2-TZVP binding energy by subtracting the dispersion interaction energy. Local hydrogen bond energies deduced from the dimer structures are found to be suitable to estimate total hydrogen bond energies in similar environments. The binding energies of OH…NH and OH…OC bonds are -9.5 and -7.1 kcal/mol, respectively. This suggests that the higher clusters are formed through OH…NH bonds as they confer more stability. Analysis of bonding in the tetramer shows that the low-energy tetramer and higher clusters are formed through OH…NH mode of hydrogen bonding, unlike the dimer which is formed through NH…OC bond. Feasibility of amino acid cluster to function as precursor for polypeptide formation is examined since the orientation of the OH…NH mode of hydrogen bonding is suitable for chemical condensation. The propensity of forming coiled structures in higher clusters and thus in the polypeptides is examined based on conformational stability in the tetramer of alanine. 1 ACS Paragon Plus Environment

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1. Introduction Amino acids are the fundamental units leading to the formation of peptides and proteins. In living organisms, peptides and proteins are formed through enzymatic actions1.Chemical evolution is considered as an important step on the pathway to life leading to biological evolution2,3. Peptide bond formation by chemical condensation of two amino acids is thermodynamically not favoured in aqueous conditions such as the seafloor hydrothermal systems3,4. The mechanism for the condensation of α- amino acids into polypeptides before the emergence of enzymes is intriguing. Several studies have focussed on the formation of peptides on mineral surfaces, metal oxides and metal ions in order to understand the plausible mechanisms for the formation of prebiotic peptides5-9. A comparative study of the peptide bond formation on oxide surfaces led to a complex reaction mechanism that was not conducive for peptide chain elongation9. A recent quantum chemical analysis on the interaction of L-alanine with zinc oxide has proved that alanine behaves like a bidentate ligand and forms two coordinate covalent bonds with zinc.10 The resulting complex possesses large stability and it is not likely to be an intermediate on the pathway for peptide bond formation. Investigations on the formation of gas-phase polypeptides from amino acid clusters containing n monomeric units, Mn, are scarce11, 12. Dipeptides were detected from gas-phase clusters of L-amino acids using low-energy collision-induced dissociation tandem mass spectrometry analysis12. Though clusters of varied sizes were generated by electrospray ionization, in-source collision induced dissociation led to the fragmentation of the larger clusters into dimer clusters12. This was attributed to lower stability of the larger clusters. Dipeptide was formed from the dimer cluster by removal of a water molecule. The gas-phase

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environment inside the collision cell was considered to simulate the probable prebiotic conditions and the authors have concluded that the dipeptides might be the precursors to the higher proteins during the prebiotic period12. Amino acid clusters of smaller size such as the dimer, M2, and the tetramer, M4, and larger clusters up to M64 were observed in different electrospray and sonic spray ionization experiments12-16. Chiral selectivity was found to play an important role in cluster formation1417

. Sublimation studies carried out on the solid amino acids have confirmed that most of the

naturally occurring amino acids formed dimer and tetramer clusters in abundance

17

.

Although there is paucity of data on the formation of gas-phase polypeptides, it is remarkable that glycine tetra peptide and proline tripeptide were detected in the collision cell experiment12. It is of considerable interest to examine the feasibility of elongated peptide formation directly from the larger clusters in the gas-phase, in order to understand their role in prebiotic chemistry. Besides the stability of the clusters, the orientations of the functional groups –COOH and –NH2 between the adjacent amino acids can play a vital role in the formation of peptide linkages leading to polypeptide. Thus it is necessary to study the stability and the structures adopted by the larger clusters to unravel their participation as precursors in the prebiotic synthesis of polypeptides. A comprehensive understanding of the stability and structure in the clusters of amino acids can be gained by the application of quantum chemical techniques. The present study is aimed at understanding the self-assembly and stability in the dimer and tetramer clusters of L-alanine in the gas-phase. Detailed analysis of the structure and bonding in these aggregates was carried out using accurate quantum chemical methods. The stability of the tetramer versus that of the dimer was probed to understand the probable role of the tetramer as a precursor for tetra peptide formation.



When n-number of amino acid monomers form the cluster, Mn, the self-assembly is driven by the interplay of several weak noncovalent interactions (NCI)18. The NCI acting between two monomers are classified into electrostatic interaction, exchange repulsion, induction, dispersion, and second-order exchange terms according to the symmetry adapted perturbation theory (SAPT)19. These interactions have varying importance in determining the structure and stability in large molecular systems such as the aggregates, metal complexes, guest-host complexes, condensed matter and biological systems18-23. Hydrogen bonding24 and the dispersion interactions22,23 are two prominent NCI which play a key role in the conformational stability and function of biological systems25. Hydrogen bonding is predominantly electrostatic in origin though in short ranges it can exhibit significant covalent nature due to orbital overlap24. The London dispersion interaction originates from induced dipole – induced dipole interaction22. In principle, the dispersion forces act in all systems and the dispersion interaction energy between two molecules is obtained by the second order perturbation energy with doubly excited (each monomer singly excited) wavefunctions of the composite system19 . Systems bound by the NCI are interesting since the interactions are weak enough to allow flexibility in adopting different conformations. The interplay of different NCI in the different conformations leads to subtle changes in the structures resulting in changes in their properties and functions. Understanding and ultimately controlling the self-assembly of molecules leading to formation of larger structures requires extensive study of these interactions. The binding energy, BE, in the non-covalently bound system can be determined directly as a sum of the different interaction energy terms using the SAPT19. Application of SAPT is straight forward for studying the dimers. The perturbational treatment is more demanding and is complicated when more than two monomers interact. However, the larger aggregates can be conveniently handled by the supermolecular treatment25. 4 ACS Paragon Plus Environment

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2. Method The interaction energy, ∆Eint(Mn), in the cluster Mn is given by the difference between the total energy of Mn and the total energies of n monomers according to the supermolecular treatment25. ∆Eint(Mn)=Etotal(Mn) –nEtotal(M)

(1)

The interaction energy given by the supermolecular treatment takes into account all the interactions operating in the cluster. However, it is not straightforward to decompose the interaction energy into the individual components. The binding energy, BE(Mn), is obtained when the total energies are corrected for the zeropoint vibrational energy (ZPE) and the basis set superposition error (BSSE) 26. BE(Mn) = ∆Eint(Mn) +∆ZPE -EBSSE

(2)

where ∆ZPE = ZPE(Mn) –nZPE(M).

(3)

BSSE is the over-binding of the cluster as each monomer utilises extra basis functions from the remaining monomers. The over-binding is attractive energy and it has to be subtracted from the binding energy. This over-binding is absent in complete basis set (CBS) limit. In the present study we ignore the BSSE correction as we include large basis sets in the energy calculations, as justified in earlier studies27,28 . Since the major NCI in biological systems originate from the hydrogen bond (HB) and the dispersion interactions, we can express the binding energy in the amino acid clusters as BE(Mn) = EHB(Mn) + ∆Edisp + ∆int

(4)

where EHB(Mn) gives the hydrogen bond energy and ∆Edisp is the dispersion interaction energy. ∆int in equation (4) corresponds to the sum of the first order exchange energy, which



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is a repulsive interaction, and attractive induction and second order exchange energy terms19. ∆int is small, in general, due to the opposing nature of the contributing terms. ∆Edisp is the difference between the dispersion energies in the cluster Edisp(Mn) and in the monomers nEdisp(M). ∆Edisp(Mn) = Edisp(Mn) – nEdisp(M)

(5)

Analysis of the results in the present study for the lowest energy alanine dimer (Ala2-A in Results and discussion section) reveals that ∆int is indeed negligible. From Equation (4) the HB energy in the amino acid cluster is EHB(Mn) = BE(Mn) - ∆Edisp

(6)

The binding energy in the clusters can be accurately determined by quantum mechanical approach using the coupled-cluster theory with single, double, and perturbative triple excitations (CCSD(T)) extrapolated to the completed basis set (CBS) limit25,29-30. However, due to heavy computational demand, the CCSD(T) method can be applied for molecules of up to ∼50 atoms. Domain based local pair natural orbital CCSD(T), (DLPNOCCSD(T)), developed by Neese and co-workers is a viable tool to study larger systems to chemical accuracy28. Computationally efficient density functional theory (DFT) treatments such as the meta hybrid M052X31 and double hybrid B2PLYP32 methods were reported to be suitable to study NCI in large molecules.

In the present study, different dimer and tetramer geometries of L-alanine were generated starting from the lowest energy gas-phase L-alanine conformer, Ala-I33. These structures were subjected to complete structural optimization in the gas-phase using the DFT methods M052X31, B2PLYP32 and the widely used B3LYP34,35. The suitability of the DFT with different basis sets was tested by computing Ala-I for which accurate experimental and


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theoretical CCSD(T)/CBS results were reported33. The comparative analysis reveals that the geometry predicted by the B2PLYP/def2-TZVP method shows best agreement with the experimental geometry. The details of the basis sets used and structures obtained are reported in Sections 1 and 2 in Supporting Information. In order to predict accurately the binding energies of Ala2 and Ala4, we performed single-point DLPNO2013-CCSD(T)/def2-TZVP calculations28 including def2-TZVP/J36 and def2-TZVP/C37 auxiliary basis sets. In the case of Ala2 we also did single-point DLPNO2013CCSD(T)/def2-QZVP, including def2-QZVP/J36 and def2-QZVP/C37 auxiliary basis sets and CCSD(T)/TZVP calculations. The binding energies were obtained from the DLPNO2013CCSD(T) and CCSD(T) total energies with ZPE correction using Equation (2). ZPE was obtained at M052X/aug-cc-pVTZ level for Ala2 and at M052X/6-311++G** level for Ala4. The dispersion energies were computed by Grimme’s D3 method which is based on the atom-pairwise dispersion scheme38. Benchmark studies39 showed that the D3 scheme at the DFT/M062X40 level yielded reliable results in a variety of molecular systems. We performed single point M062X-D3/def2-QZVP calculations on the structures optimized at M052X/6-311++G** level. The M062X-D3 calculations included the auxiliary def2QZVP/J36 basis set. To enhance the efficiency of the M062X-D3, B2PLYP and the DLPNO2013-CCSD(T) calculations, combination of the resolution of identity (RI) and the “chain of spheres exchange” algorithms (RIJCOSX)41,42 were used. The B3LYP and M052X calculations were done using the Gaussian 03 software43. B2PLYP, M062X-D3, DLPNO2013-CCSD(T) and CCSD(T) calculations were performed by the ORCA 3.0.3 software44. NormalPNO thresholds were used in the DLPNO2013-CCSD(T) calculations.

3. Results and Discussion



The structure of L-alanine monomer predicted by the B2PLYP/def2-TZVP method showed very close agreement with the accurate experimental gas-phase structure (Section 2 in Supporting Information). The B2PLYP/def2-TZVP optimized geometries of Ala2 and Ala4 are shown in Figures 1 and 2 respectively. The optimized alanine dimer structures Ala2-A, Ala2-B, Ala2-C and Ala2-D are presented in Figures 1a, 1b, 1c and 1d respectively. The different dimer and tetramer structures given in Figures 1 and 2 correspond to energy minima on the potential energy surface as proved by all positive vibrational frequencies at M052X/6-311++G** level. Selected structural parameters of the different DFT optimized geometries are compared in Tables S2 and S3 for Ala2. The total energies and interaction energies of Ala2 predicted by the DFT methods are given in Table S4 in Supporting Information. The CCSD(T) and DLPNO2013-CCSD(T) energies of Ala2 are presented in Table S5 in Supporting Information. The structural parameters of Ala4 corresponding to B2PLYP/def2-TZVP optimized geometries are compared in Table S6 in Supporting Information. DFT and DLPNO2013-CCSD(T) energies of Ala4 are listed in Tables S7 and S8 respectively. The alanine monomer components are labelled as I and II in the dimer (Figure 1) and I, II, III and IV in the tetramer (Figure 2). These labels are used to identify the donor and acceptor centres of the HBs.

3.1. Structure and stability in alanine dimer The dimer geometries Ala2-A, Ala2-B, Ala2-C and Ala2-D (Figure 1) are generated such that they represent the typical hydrogen bonding modes possible between the two monomer units. These hydrogen bonds are localised between three centers D-H…A where D and A are hydrogen bond donor and acceptor, respectively24. The HB lengths and angles are presented in Figure 1. Though each of the dimer structure possesses two hydrogen bonds, their strengths differ as seen from the values of HB lengths and angles (Figure 1). The HBs, OH(I)…OC(II) and OH(II)…OC(I) in Ala2-A and the O-H(I)...NH(II) in Ala2-B are linear 8 ACS Paragon Plus Environment

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with the HB angles in the range 179.4 – 179.8°. The HB lengths are 1.652 Å in Ala2-A and 1.739Å in Ala2-B. They are strong HBs having covalent bond orders > 0.145. The higher bond order 0.17 for OH...NH in Ala2-B reflects that it is stronger than the OH…OC bond in Ala2-A.The second HB in Ala2-B, CH(II)…OC(I) is weak as reflected by the long HB length (2.430 Å ) with large deviation from linearity (∠CH...O = 128.4°). The two equivalent NH…OC bonds in Ala2-C are of medium strength as the HB lengths are longer (2.351Å) and deviate considerably from linearity with HB angle of 144.1°. The NH…OC and NH…NH bonds in

Ala2-D are also of medium strength. The binding energies of the

different modes of HBs are deduced in Equations (7) – (11) from the total HB energies.

Figure 1. B2PLYP/def2-TZVP (B2PLYP-1) optimized structures of alanine dimer: (a) Ala2-A; (b) Ala2-B; (c) Ala2-C; (d) Ala2-D. HB lengths in Å and HB angles in ° are shown. Strong hydrogen bonds are indicated by green dotted lines. Medium / weak hydrogen bonds are shown by purple lines. Covalent bond orders of the strong hydrogen bonds are shown in bold italics. Color code for atoms: C – grey, H – light grey, N – blue, O – red. DLPNO2013-CCSD(T) and CCSD(T) binding energies at geometries optimized at B3LYP-1 = B3LYP/6-31G*, B3LYP-2 = B3LYP/6-311++G**, M052X-1 = 9 ACS Paragon Plus Environment


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M052X/6-311++G**, B2PLYP-1 = B2PLYP/def2-TZVP and B2PLYP-2 = B2PLYP/def2-QZVP levels.

Binding energies (BEs), calculated from the DLPNO2013-CCSD(T) and CCSD(T) total energies using the DFT optimized geometries, of Ala2 are compared in Figure 1. The results reveal that Ala2-A is the lowest energy structure of the dimer and exhibit the highest magnitude of BE, according to the different levels of computations. All the methods predict the same trend in the order of stability of the structures: Ala2-A > Ala2-B > Ala2-C > Ala2-D The BE in Ala2-A is predicted in the range -14.26 to -14.66 kcal/mol by the DLPNO2013CCSD(T)/def2-TZVP calculations carried out on the different DFT optimized geometries (Figure 1). These values are in good agreement with the binding energy of -14.80 kcal/mol in the analogous acetic acid dimer obtained by CCSD(T)/CBS study46. Corresponding binding energy for Ala2-B is in the range -10.77 to -10.93 kcal/mol. Ala2-B is ~ 4 kcal/mol higher in energy than Ala2-A since one of the HBs in the former is a weak CH...OC bond. Ala2-C and Ala2-D are higher energy structures and possess binding energies, respectively, -4.40 to -5.93 and -3.35 to -4.70 kcal/mol. Table 1. Dispersion energy (Edisp) and dispersion interaction energy (∆Edisp) computed at

M062X-D3/def2-QZVP//M052X/6-311++G** level Ala-I

Ala2

Edisp

Structure

Edisp

∆Edisp

(kcal/mol)

(kcal/mol)

Ala2-A

-0.58

-0.34

Ala2-B

-0.66

Ala2-C

-0.74

(kcal/mol) -0.12

Ala4 Structure

Edisp

∆Edisp

(kcal/mol)

(kcal/mol)

LI

-1.79

-1.31

-0.42

CY1

-2.68

-2.20

-0.50

CY2

-2.95

-2.47


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Ala2-D

-0.80

-0.56

ZI1

-2.74

-2.26

CO

-2.92

-2.44

SW1

-2.75

-2.27

SW2

-2.93

-2.45

The BEs obtained by the DLPNO2013-CCSD(T)/def2-QZVP method are similar to the DLPNO2013-CCSD(T)/def2-TZVP results. As compared to the DLPNO2013-CCSD(T) results, the CCSD(T)/TZVP BEs are overestimated up to 2 kcal/mol in Ala2-B. This significant deviation may be due to the incomplete nature of the TZVP basis set used in the canonical CCSD(T) study and the truncation thresholds employed in the DLPNO2013CCSD(T) calculations. To analyse the origin of the above error, explicitly correlated47 CCSD(T) calculations with F12 correction (CCSD(T)-F12) were performed for alanine dimer structures using cc-pVDZ-F12 basis set. Resolution of identity (RI) approximation was used for the F12 part (CCSD(T)-F12/RI)

and the auxiliary basis set cc-pVTZ/C and

complementary auxiliary basis set cc-pVTZ-F12/CABS were included in the calculations. Calculations at this level are reported to yield total energies at the CBS limit48. The total energies and interaction energies obtained by the CCSD(T)-F12/RI calculations using the ORCA version 4.0.x49 are given in Table S10 in the Supporting Information. Further, the DLPNO2013-CCSD(T) results generated in the present study using the ORCA version 3.0.3 were based on the default NormalPNO thresholds. Accuracy consideration of the DLPNO– CCSD(T) method has shown that the TightPNO and VerytightPNO thresholds are better suited to study the noncovalent interactions50. Neese and coworkers have applied the “Sparse maps” concept51-55 in the recent DLPNO-CCSD(T) implementation in the ORCA version 4.049 which is more efficient than the DLPNO2013 method. We have analysed the effect of 11 ACS Paragon Plus Environment


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NormalPNO and TightPNO thresholds in the DLPNO-CCSD(T)/def2-TZVP interaction energies of alanine dimer structures optimized by the B2PLYP/def2-TZVP method. These interaction energies are compared with the CCSD(T)-F12/RI results in Table S10

in

Supporting Information. It is seen that the deviation from the reference CCSD(T)-F12/RI results are well within 1 kcal/mol when TightPNO thresholds are used in the DLPNOCCSD(T) method. We have analysed the trend in the stability of Ala2 structures by examining the contributions of the HB and dispersion interaction energies. Dispersion energies obtained by the M062X-D3/def2-QZVP//M052X/6-311++G* calculations are listed in Table 1. The dispersion interaction energy ∆Edisp in the structures Ala2-A, Ala2-B, Ala2-C and Ala2-D are -0.34, -0.42, -0.50 and -0.56 kcal/mol respectively. The contribution of dispersion interaction energy to the binding in Ala2-A is about 2% though it is >10% in Ala2-D. Table 2. Binding energies and HB energies in dimer and tetramer of alanine at DLPNO2013CCSD(T)/def2-TZVP level BE (kcal/mol)

HB energy (kcal/mol)

B3LYP/6-

M052X/6-

B2PLYP/def2- B3LYP/6-

M052X/6-

B2PLYP/def2-

311++G**

311++G**

TZVP

311++G**

311++G**

TZVP

Ala2-A

-14.61

-14.36

-14.54

-14.27

-14.02

-14.20

ala2-B

-10.77

-10.62

-10.88

-10.35

-10.22

-10.46

ala2-C

-4.40

-5.93

-5.85

-3.90

-5.43

-5.35

ala2-D

-4.34

-4.70

-4.69

-3.78

-4.14

-4.13

LI

-33.06

-33.90

-33.51

-31.75

-32.59

-32.20

CY1

-41.85

-42.67

-42.34

-39.65

-40.47

-40.14

Dimer

Tetramer


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CY2

-40.17

-41.34

-40.92

-37.7

-38.87

-38.45

ZI1

-41.38

-42.13

-42.07

-39.12

-39.87

-39.81

CO

-35.06

-36.44

-36.13

-32.62

-34.00

-33.69

SW1

-36.22

-37.78

-37.50

-33.95

-35.51

-35.23

SW2

-36.04

-37.57

-37.59

-34.07

-35.60

-35.62

Table 2 lists the DLPNO2013-CCSD(T)/def2-TZVP predicted BE and HB energy for the structures optimized by the B3LYP/6-311++G*, M052X/6-311++G* and B2PLYP/def2TZVP methods. The HB energy in a given dimer structure is generated by subtracting the dispersion energy from the binding energy, using equation (6). The HB energy for the B2PLYP optimized Ala2-A is -14.20 kcal/mol. The HB network in Ala2-A is similar to that observed in carboxylic acid dimers with two equivalent OH…OC bonds. Kollipost et al. 56 obtained accurate dissociation energy of 14.22±0.12 kcal/mol in formic acid dimer. Kalescky

et al. 27 reported the BE of -14.32 kcal/mol in formic acid dimer by accurate CCSD(T)/CBS study. It is striking that the HB energy of -14.20 kcal/mol predicted by the DLPNO2013CCSD(T)/def2-TZVP//B2PLYP/def2-TZVP study in Ala2-A agrees very well with the experimental BE in formic acid dimer (-14.22±0.12 kcal/mol), which arises exclusively due to the two OH...OC bonds. This agreement validates our assumption of neglecting the sum of first-order exchange, induction and second order exchange interaction terms in alanine dimer (∆int = 0.0 in Equation 4). The present analysis provides support to the DLPNO2013CCSD(T)/def2-TZVP//B2PLYP/def2-TZVP theoretical model to study accurately the amino acid clusters. We use the results obtained from this method in the discussions that follow. It is inferred that each OH...OC bond in the formic acid dimer as well as in Ala2-A stabilizes the dimer by 7.1 kcal/mol (EHB(OH…OC) = -7.1 kcal/mol). The HB energy of 10.46 kcal/mol in Ala2-B arises from a strong OH...NH and a weak CH...O=C bonds. The 13 ACS Paragon Plus Environment


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binding energy for the CH...OC bond in acetic acid dimer46 and the CH...O interaction in the smallest methane - water system57 was reported to be

~ - 1.0 kcal/mol by extensive

CCSD(T)/CBS study. Hence we use the C-H...OC binding energy of -1.0 kcal/mol in Ala2-B. This leads to an estimated OH...NH binding energy of ~ -9.5 kcal/mol. The larger magnitude of binding in the O-H...NH bond in Ala2-B than that of the OH...OC in the structure Ala2-A is supported by the higher covalent bond order of 0.17 in the former. The local binding energy for the different modes of HBs in the Ala2 structures by the DLPNO2013CCSD(T)/def2-TZVP//B2PLYP/def2-TZVP calculations are given in the following equations:

Ala2-A EHB(Ala2-A) = 2EHB(OH…OC) = -14.20 kcal/mol ; EHB(OH…OC) = -7.1 kcal/mol

(7)

Ala2-B EHB(Ala2-B) = EHB(OH…NH) + EHB(CH…OC) = -10.46 kcal/mol; EHB(CH…OC) = -1.0 kcal/mol46,57 (8) EHB(OH…NH) = -9.5 kcal/mol

(9)

Ala2-C EHB(Ala2-C) = 2EHB(NH…OC) = -5.35 kcal/mol; EHB(NH…OC) = -2.7 kcal/mol Ala2-D EHB(Ala2-D) = EHB(NH…OC)+EHB(NH…N-H) = -4.13 kcal/mol; EHB(NH…OC) = -2.7 kcal/mol


(10)

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EHB(NH…NH) = -1.4 kcal/mol

(11)

The above binding energies for the local HBs in alanine dimer are useful indicators in estimating the total HB energies in similar environment wherein the hydrogen bonding interaction is localized.



3.2. Structure and stability in alanine tetramer The low energy structures of Ala4 at the B2PLYP/def2-TZVP level (Figure 2) illustrate the different three dimensional arrangements in the tetramer. The linear structure LI is formed from the monomers through strong OH…NH bond between I and II, II and III and III and IV, which is an extension of Ala2-B (dimer of Ala2-B). The coil structure CO is formed similarly but the HB network is arranged to form a coil. The LI and CO have 3 OH…NH bonds with binding energies -33.51 and 36.13 kcal/mol respectively (Figure 3 and Table 2). Coiling of Ala4 leads to two NH…OC hydrogen bonds of medium strength, instead of three weak CH…OC interactions in LI, and the structure CO is more stable than LI. In cyclic structures CY1and CY2, in addition to the 3(OH…NH) HBs between the successive monomers, there is HB formation between I and IV. The alanine units IV and I are bonded through OH(IV)…OC(I) and OH…NH, respectively, in CY1 and CY2. The structure CY2 with four OH…NH bonds is expected to possess the lowest energy (from the consideration of BEs of local HBs). However Figures 2 and 3 reveal that the energy of CY1 is lowered due to gain in the strength of the OH(I)…NH(II) bond with increased covalent bond order 0.27 and the formation of a new NH(II)…OC(IV) bond. The BEs of CY1 and CY2 are -42.34 and -40.92 kcal/mol, respectively. The tetramer structures SW1 and SW2, generated from the lowest energy dimer Ala2-A (dimer of Ala2-A), have higher energies than the cyclic structures. The carboxylic acid dimer units in SW1 and SW2 are in a displaced parallel arrangement. This leads to pi-pi stacking interactions besides the 4 strong OH…OC bonds and the binding energies are -37.50 and 37.59 kcal/mol respectively. In addition to the strong HBs described above, weak HBs are also present in the tetramer structures as seen from Figure 2.


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Figure 2. B2PLYP/def2-TZVP optimized geometries of alanine tetramer in the linear (LI), cyclic (CY1, CY2), zwitter-ionic (ZI1), coil (CO) and sandwich (SW1, SW2) structures. Hydrogen bonds between the alanine units are denoted by green dotted lines. Purple lines indicate weak hydrogen bonds. HB lengths in Å and HB angles in ° are shown. Covalent bond order of HB larger than 0.1 is indicated in bold italics. 17 ACS Paragon Plus Environment


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Besides these structures wherein the alanine units are neutral, intermolecular zwitterion like tetramers ZI1 and ZI2 having structures similar to the cyclic counterparts CY1 and CY2 are also characterized in the gas-phase. In ZI1, the amino nitrogen of alanine(II) abstracts hydrogen from COOH(I) leading to reorganization of the bonds in this region. Though the BE in ZI1 is very close to that of CY1, ZI2 is found to be a higher energy structure. The optimized geometries of some higher energy structures are presented in Figure S2 in Supporting Information. The hydrogen bonding network in the alanine tetramer structures and the estimated total HB energies, based on the binding energies of the local hydrogen bonds in Equations (7-11), are listed in Table 3. Table 3. Number of hydrogen bonds and the estimated total hydrogen bond energy (kcal/mol) in alanine tetramera

NH…OHb

EHB

OH…OC

OH…NH

NH…OC

NH…NH

CH…OC

LI

0

3

0

0

3

0

-31.5

CY1

1

3

1

0

1

0

-39.3

CY2

0

4

0

0

1

0

-39.0

(Estimated)

1 strongc ZI1

1

2

1 medium

0

1

0

-39.3

CO

0

3

2

0

0

0

-33.9

SW1

4

0

0

2

2

0

-33.2

SW2

4

0

0

0

0

4

-32.4

a

EHB(OH…OC) = -7.1 kcal/mol; EHB(OH…NH) = -9.5 kcal/mol; EHB(NH…OC) = -2.7 kcal/mol; EHB(NH…NH) = -1.4 kcal/mol; EHB(CH…OC) = -1.0 kcal/mol; EHB(NH…OH) = -1.0 kcal/mol b The NH…OH interactions in SW2 have HB length = 2.647 Å and HB angle =138.2° and are weak in nature. Hence we assigned HB energy of -1.0 kcal/mol to this HB similar to that of CH…OC. c

The strong NH(II)…OC(I) bond in ZI1 is assigned HB energy of -9.5 kcal/mol similar to that of OH…NH.


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Among the structures examined for Ala4, the cyclic structure CY1 is predicted to be the lowest energy structure by the B3LYP, M052X and B2PLYP methods (Figure 3 and Table 2). Interestingly, the trend in the stability of the low-energy tetramer structures is the same for the different DFT methods studied: CY1 > ZI1 > CY2 > SW1 ~ SW2 > CO > LI The BEs in the B2PLYP/def2-TZVP optimized Ala4 structures are examined with reference to BE of two lowest energy dimers 2Ala2-A, i.e., -29.08 kcal/mol. The tetramer structures possess BE < -33.kcal/mol and are more stable than 2Ala2-A. The lowest energy tetramer CY1 has BE -42.34 kcal/mol with additional stability of 13.26 kcal/mol, as compared to 2Ala2-A,

which is significant indeed. This observation contradicts the claim of Singh et

al.12 that the larger clusters are less stable than the dimer.

Figure 3. Binding energy (kcal/mol) in Ala4 (Figure 2) by DLPNO2013-CCSD(T)/def2TZVP calculation performed on the B3LYP/6-311++G**, M05-2X/6-311++G** and B2PLYP/def2-TZVP optimized geometries



Comparison of the energies in the alanine tetramer at DLPNO-CCSD(T)/def2TZVP//B2PLYP/def2-TZVP with TightPNO and NormalPNO thresholds (Table S8 in Supporting Information) reveals that the interaction energies have increased in magnitudes as compared to the corresponding DLPNO2013 results. When TightPNO threshold is used IE has increased in magnitude by ~ 3.0 kcal/mol in the lowest energy structure CY1. The dispersion interaction energy ∆Edisp in the tetramer structures are in the range 1.3 to -2.5 kcal/mol (Table 1). The dispersion contribution has increased in the tetramer structures, compared to that in the dimer, as expected from the larger size. The linear structure LI has the lowest contribution of ~ -1.3 kcal/mol since the methyl groups are farther apart and the structure is sterically not hindered23. HB energies in the Ala4 structures obtained from Equation (6) are in the range -32.2 to -40.1 kcal/mol (Table 2). Clearly the HB energy plays a dominant role in stabilizing the tetramer. The total HB energies estimated from the local HB energies (Table 3) and the computed values given in Table 2 agree within 1 kcal/mol for the structures LI, CY1, CY2, CO and ZI1. This proves the utility of the local HB energies (Equations (7-11)) for reliable estimates of total HB energies in similar environments. The HB energies estimated in the sandwich structures deviate >2 kcal/mol since the stacking interaction is not taken into account while computing the HB energy in Table 2.

3.3. Peptide bond formation from L-alanine dimer and tetramer clusters Peptide bond is formed by chemical condensation involving the COOH and NH2 groups of two amino acids. It is evident that peptide linkage is feasible in the cluster structures formed by OH…NH hydrogen bonds due to the close proximity of OH and NH2 functional groups. The OH…NH hydrogen bonds in the cluster need to be broken and atoms in the functional groups have to be re-oriented for chemical condensation to yield peptide


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linkage. Inspection of the four dimer structures reveals that Ala2-B alone has the required geometry for condensation though it is a high energy structure. The observation of dipeptide in the low-energy collision induced dissociation study12 reveals that alternate OH…NH hydrogen bonds in the higher cluster were broken to yield dimer having the HB network similar to Ala2-B, from which the dipeptide was formed. Characterization of glycine tetrapeptide in the gas-phase study12 shows that it might have formed directly from the tetramer cluster. Clearly, formation of alanine tetrapeptide is feasible from the tetramer structures LI, CY1, CY2, CO under suitable conditions. The sandwich structures SW1 and SW2, however, are not suitable for peptide formation similar to the dimer Ala2-A as they lack OH…NH hydrogen bonds. CY1 and CY2 can give rise to cyclic peptides.

LI and CO can generate,

respectively, the strand and the helical / random coil secondary structures by removal of three water molecules. The coil conformer of the tetrapeptide can retain the two NH…OC bonds that are present in the coil cluster. It is well known that NH…OC hydrogen bonds between amino acid residues play a central role in stabilizing the α-helical, 310 helical and random coil secondary structures in peptides1,58. As the size of the cluster increases the number of NH…OC bonds in the coil arrangement will increase. This would lead to the dominance of the coil cluster as it would possess lower energy than the linear or cyclic clusters. This inference can account for the origin of coiling in polypeptides and has prebiotic relevance.

4. Conclusions It is of interest to note that the lowest energy dimer Ala2-A is formed by the OH…OC bonds and is not suitable for peptide bond formation. The low-energy tetramer structures CY1, CY2, ZI1, CO and LI are formed mainly through OH…NH bonds and are more stable than 2Ala2-A. Our analysis reveals that hydrogen bonding is the dominant force for cluster



formation in L-alanine. Local HB energies deduced from the dimer structures (Equations (711)) are suitable to estimate total HB energies in similar environments. The binding energies of OH…NH and OH…OC bonds are -9.5 and -7.1 kcal/mol, respectively. This suggests that the higher clusters are formed through OH…NH bonds as they confer more stability. Comparative analysis of the binding in the tetramer structures leads to the conclusion that the coil structure is more stable than the linear structure due to the presence of two NH…O=C bonds. It may be inferred that in the larger clusters, the stability of the coil arrangement will exceed that of the cyclic and linear arrangements due to formation of more NH…O=C bonds. It is well known that peptides and proteins adopt coil structures (helical coil, random coil, 3-10 helical coil etc.) which are stabilized by the NH…O=C bonds. This hints at the feasibility of formation of higher peptides in the gas-phase directly from the amino acid clusters, under appropriate (prebiotic) conditions. Dipeptides were detected from gas-phase clusters of L-amino acids using low-energy collision-induced dissociation tandem mass spectrometry analysis12. It is inferred that suitable energy for the collision induced dissociation might dissociate the OH…NH bonds in the higher clusters and lead to higher polypeptide by condensation. Though dipeptides of Lamino acids were observed in the collision cell, it is indeed encouraging to note that glycine tetrapeptide and proline tripeptide were also detected in the experimental study12. Though the DLPNO2013-CCSD(T)/B2PLYP/def2-TZVP results are found to be reliable, it is observed that DLPNO2013-CCSD(T) binding energies generated by M052X method agree within 0.2 kcal/mol. Even the B3LYP method, which is not a suitable choice for studying NCI, yields results comparable with those of the B2PYLP and M052X methods in structures bound through strong hydrogen bonds (Table 2). Though the B3LYP method shows larger deviation (~1.0 – 1.5 kcal/mol) in floppy structures bound by weak hydrogen


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bonds, the DLPNO2013-CCSD(T)/B3LYP energies predict correct trend in the relative stability and it can be used for studying large systems due to the computational efficiency.

Supporting Information Selected structural parameters

of the different DFT optimized geometries of L-alanine

monomer, dimer and tetramer and their total energies, interaction energies, zero-point vibrational energies, basis set superposition error analysis and Cartesian coordinates of optimized geometries are presented in Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. Author Contributions E.J.P.M. conceived and designed the study, generated the input geometries, carried out the computations, analysed the results and written the manuscript. P.D. carried out computations on the alanine tetramer at B3LYP and M052X levels.

Competing financial interests The authors declare no competing financial interests.

Corresponding author Correspondence to E.J. Padma Malar

Acknowlegement EJPM thanks the University Grants Commission, New Delhi, India for financial support through Award Number F.8-22/SA-I/90 and Professor Daksh Lohiya, Department of Physics and Astrophysics, University of Delhi for useful discussions. The authors are grateful to Professor Frank Neese and Dr. Yang Guo, Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany for valuable discussions and for providing the CCSD(T)-F12 results.



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Structural Stability in Dimer and Tetramer Clusters of L-alanine in the

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