Supporting information

Molecular Insight from DFT Computations and Kinetic

Measurements into the Steric Factors Influencing Peptide Bond

Hydrolysis Catalyzed by a Dimeric Zr(IV)-Substituted Keggin Type

Polyoxometalate

Tzvetan T. Mihaylov,*† Hong Giang T. Ly,‡ Kristine Pierloot† and Tatjana N. Parac-Vogt‡

† Laboratory of Computational Coordination Chemistry, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.

‡ Laboratory of Bioinorganic Chemistry, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.

Figure S1. 1H NMR spectra of Gly-Gly recorded at different time increments for the reaction

between 2.0 mM Gly-Gly and 2.0 mM 1 at pD 5.4 and 60 °C.

Figure S2. 1H NMR spectra of Gly-Ala recorded at different time increments for the reaction

between 2.0 mM Gly-Ala and 2.0 mM 1 at pD 5.4 and 60 °C.

Figure S3. 1H NMR spectra of Gly-Ala recorded at different time increments for the reaction

between 2.0 mM Gly-Ala and 2.0 mM 1 at pD 5.4 and 60 °C.

Figure S4. 1H NMR spectra of Gly-Leu recorded at different time increments for the reaction

between 2.0 mM Gly-Leu and 2.0 mM 1 at pD 5.4 and 60 °C.

Figure S5. 1H NMR spectra of Gly-Ile recorded at different time increments for the reaction

between 2.0 mM Gly-Ile and 2.0 mM 1 at pD 5.4 and 60 °C.

Figure S6. 1H NMR spectra of Gly-Phe recorded at different time increments for the reaction

between 2.0 mM Gly-Phe and 2.0 mM 1 at pD 5.4 and 60 °C.

Computational details

The aqueous phase free energy (𝐺!"∗ ) of the species was estimated as

𝐺!"∗ = 𝐸!"!"#$% + 𝐸!"#$!"#$ + 𝐺! − 𝐸!" !"#$ + ∆𝐺!"#$∗ + ∆𝐺!→∗ (1)

where 𝐸!"!"#$% is the SP B3LYP/def2-TZVP electronic energy, 𝐸!"#$!"#$ is the D3BJ dispersion

correction and ∆𝐺!"#$∗ is the free energy change due to hydration, as derived from the COSMO model (at the B3LYP/def2-TZVP level, including a correction for the solute charge density lying outside the cavity). The 𝐺! − 𝐸!" !"#$ term denotes the thermochemical corrections (1 atm, 298.15 K) derived from the BP86 frequency calculations. The last term in Eq. 1, ∆𝐺!→∗, is the standard state correction accounting for the free energy change of 1 mole of ideal gas from 1 atm (24.46 L mol-1) to 1 M (1 mol L-1). At 298.15 K, ∆𝐺!→∗ is 1.89 kcal mol-1.1 Energy terms are collected in Table S3.

For the reactions of 1 with Gly-Gly we assume that in solution, at near neutral pH, the POM retains both Zr-coordinated H2O molecules (as in the crystal structure), while the major form of the ligand is the zwitterionic form (pKa1 = 3.13, pKa2 = 8.25).2 However, in order to coordinate to a Zr-atom the terminal amino group of the Gly-Gly zwitterion (–NH3

+) needs to be deprotonated. Therefore, to estimate the stability of such coordination modes the anionic form of Gly-Gly was considered as a reactant instead of the zwitterionic form. The reactions of complexation between Gly-Gly and 1 can be generally expressed as

[Gly-Gly]q (aq, 1 M) + [{α-PW11O39Zr(µ-OH)(H2O)}2]8- (aq, 1 M) →

[{α-PW11O39Zr(µ-OH)}2(Gly-Gly)](8 + q)- (aq, 1 M) + 2 H2O (aq, 1 M) (2)

where the value of q depends on the Gly-Gly binding mode. It is either -1 (Gly-Gly anion) when the terminal amino group coordinates to a Zr-atom or 0 (Gly-Gly zwitterion) when this group remains uncoordinated (and retains its –NH3

+ protonation state). The stability of each complex is then calculated as

∆𝐺!"!"#$% = 𝐺!"∗ α− PW!!O!"Zr µ− OH ! Gly− Gly + 2𝐺!"∗ H!O − 𝐺!"∗ Gly− Gly −

𝐺!"∗ α− PW!!O!"Zr µ− OH H!O ! + 2𝑅𝑇 ln H!O (3)

where RTln([H2O]) is a concentration correction term accounting for the free energy change of 1 mole of H2O gas from 1 M to the standard state concentration of the liquid water, 55.34 M. At 298.15 K, RTln(55.34) = 2.38 kcal mol-1.1,3 For the reactions involving the Gly-Gly anion a correction must be introduced in order to account for the free energy change due to the –NH3

+ deprotonation at a certain pH.

∆𝐺!"!"#$% pH = ∆𝐺!"

!"#$% + ∆𝐺!"#$%&(pH) (4)

∆𝐺!"#$%& pH = 2.303𝑅𝑇 p𝐾! − pH = −∆𝐺!"#$(pH) (5)

where pKa is the pKa value of the Gly-Gly –NH3+ group (8.25) and pH is the environmental pH,

namely 6.4. The pH value of 6.4 was chosen to be able to compare the theoretical results with the suggested coordination mode of Gly-Gly to 1 based on 13C NMR measurements (previously performed by us) at this pH.4

For the reactions involving the monomeric compound, α-PW11O39Zr(OH)(H2O) (2), the formation of a complex with Gly-Gly zwitterion is given by the following reaction

[Gly-Gly]± (aq, 1 M) + [α-PW11O39Zr(OH)(H2O)]4- (aq, 1 M) →

[α-PW11O39Zr(OH)m(H2O)n(Gly-Gly)]4- (aq, 1 M) + (2 - m - n) H2O (aq, 1 M) (6)

where, depending on the ligand binding mode m can be either 0 (where the Zr-OH ligand has received a proton from the substrate -NH3

+ group) or 1. For m = 0, n = 0, 1 or 2 while for m = 1, n is either 0 or 1. The corresponding free energy change is calculated as

∆𝐺!"!"#$% = 𝐺!"∗ α− PW!!O!"Zr OH ! H!O ! Gly− Gly + 2−𝑚 − 𝑛 𝐺!"∗ H!O −

𝐺!"∗ Gly− Gly − 𝐺!"∗ α− PW!!O!"Zr OH H!O + 2−𝑚 − 𝑛 𝑅𝑇 ln H!O . (7)

Depending on the Gly-Gly binding mode and the number of ligands the acidity of the Zr-coordinated water could change substantially. Thus, the coordination compounds obtained according to reaction (6) may undergo additional deprotonation/protonation of the coordinated H2O/OH− ligand, favored by the environmental pH, which in turns will affect their stability. Because of the lack of experimental data, the Zr-H2O protonation state in the parent compound 2 and its Gly-Gly complexes at pH 6.4 was elucidated by making use of pKa values of the coordinated water molecules obtained from the reaction:

ComplH (aq, 1 M) → Compl (aq, 1 M) + H+ (aq, 1 M) (8)

p𝐾! =!!"∗ !"#$% ! !!"∗ !! ! !!"∗ !"#$%&

!.!"!!". (9)

where, 𝐺!"∗ ComplH and 𝐺!"∗ Compl were computed according to Eq. (1), while for the 𝐺!"∗ H! the value of 270.29 kcal mol-1 was adopted (that is the sum of the standard (1 atm, 298.15 K) free energy of a proton in gas-phase, -6.28 kcal mol-1, corrected by 1.89 kcal mol-1 to switch from 1 atm to 1 M standard state, and the free energy of H+ hydration, -265.9 kcal mol-1).5 Making use of the pKa values thus obtained, the energy contribution to the formation free energy (calculated by Eq. (7)) due to protonation/deprotonation (at pH 6.4), was accounted for by using Eqs. (4) and (5).

References

1. Bryantsev, V. S.; Diallo, M. S.; Goddard III, W. A., Calculation of Solvation Free Energies of Charged Solutes Using Mixed Cluster/Continuum Models. J. Phys. Chem. B 2008, 112, 9709-9719. 2. Dean, J. A., Lange's Handbook of Chemistry. 15th ed.; McGraw-Hill, Inc.: New York, 1999. 3. Pliego, J. R., Jr.; Riveros, J. M., The Cluster-Continuum Model for the Calculation of the Solvation Free Energy of Ionic Species. J. Phys. Chem. A 2001, 105, 7241-7247. 4. Ly, H. G. T.; Absillis, G.; Parac-Vogt, T. N., Amide bond hydrolysis in peptides and cyclic peptides catalyzed by a dimeric Zr(IV)-substituted Keggin type polyoxometalate. Dalton Trans. 2013, 42, 10929-10938. 5. Alongi, K.; Shields, G., Theoretical Calculations of Acid Dissociation Constants: A Review Article. Annu. Rep. Comput. Chem. 2010, 6, 113-138.

Table S1. Optimized vs. experimental structural parameters of 1

Bond length Theor. Expr.a Zr1-µO1 2.21 2.17(1) Zr1-µO2 2.14 2.13(1) Zr2-µO1 2.14 2.13(1) Zr2-µO2 2.21 2.16(1) average 2.17 2.15 Z1-O11 2.13 2.13(1) Z1-O12 2.13 2.14(1) Z1-O13 2.15 2.12(1) Z1-O14 2.13 2.09(1) Z2-O21 2.12 2.15(1) Z2-O22 2.14 2.12(1) Z2-O23 2.15 2.11(1) Z2-O24 2.12 2.12(1) average 2.13 2.12 Zr1-O1w 2.32 2.23(1) Zr2-O2w 2.33 2.22(1) average 2.32 2.23 O13···O2w 2.67 2.71(1) O23···O1w 2.67 2.70(2) average 2.67 2.70 Zr1···Zr2 3.643 3.571(2) Angle µO1-Zr1-µO2 66.0 67.6(4) µO1-Zr2-µO2 66.1 67.6(4) average 66.1 67.6 Zr1-µO1-Zr2 113.9 112.3(4) Zr1-µO2-Zr2 113.9 112.5(4) average 113.9 112.4

a Values taken from Nomiya et al., Dalton Trans. 2009, 5504-5511.

Coordination of Gly-Gly to compound 1

To investigate the binding properties of Gly-Gly towards 1, the most feasible bidentate modes of coordination were constructed, where the dipeptide bridges the two neighboring Zr-atoms, by varying the basic sites of Gly-Gly interacting with the metals. The optimized molecular structures and the corresponding free energies of complexation are given in Figure S7 and Table S2, respectively. In complex 1a the ligand binds to 1 via the terminal amine nitrogen and the amide oxygen atoms while in complex 1b a terminal carboxyl oxygen atom coordinates to Zr(IV) instead of the carbonyl oxygen. Both the formation of 1a and 1b requires deprotonation of the positively charged –NH3

+ group of the Gly-Gly zwitterion. When considering the reaction between 1 and the anionic form of the ligand both the formation of the complexes 1a and 1b were found to be endergonic processes, requiring 9.4 and 16.0 kcal mol-1 respectively. When taking into account the free energy required for deprotonation of the –NH3

+ group at pH 6.4 (see Eqs. (4) and (5) in section “Computational details” above) the formation free energies become even more positive, by 2.5 kcal mol-1 (11.9 and 18.5 kcal mol-1 respectively). In complexes 1c and 1d coordination of 1 with the zwitterionic rather than the anionic form of Gly-Gly is considered. The first complex is formed by bidentate bridging coordination involving oxygen atoms of both the peptide carbonyl and terminal carboxyl groups, while in the second complex the two Zr-atoms are linked through the terminal carboxyl group. In both cases the ligand –NH3

+ group forms a hydrogen bond (HB) with either a µ-OH oxygen or a terminal oxygen atom of the POM skeleton, which additionally stabilizes the complexes (formation of a HB with a bridging Zr-O-W oxygen in 1c was found to be less favorable). The calculated formation free energies of 1c and 1d (according to reaction (2), see section “Computational details” above) are 7.9 and 0.7 kcal mol-1 respectively.

Figure S7. DFT optimized structures with bidentate bridging coordination of Gly-Gly to 1.

Table S2. Formation free energy (kcal mol-1) of the coordination compounds of Gly-Gly and 1.

Complex ∆𝐺!"!"#$% ∆𝐺!"

!"#$% pH a 1a 9.4 11.9 1b 16.0 18.5 1c 7.9 - 1d 0.7 - a See Eqs. (4) and (5) in section “Computational details” above. At pH 6.4 ∆𝐺!"#$%& −NH!! = 2.5 kcal mol-1.

Table S3. Energy data (in a.u.) for 1 and 2 and their complexes with Gly-Gly.

Compound 𝐺! − 𝐸!" !"#$ 𝐸!"!"#$% + ∆𝐺!"#$∗ 𝐸!"#$!"#$ 𝐺!"a

H2O 0.003173 -76.438341 -0.000574 -76.435742 Gly-Gly± 0.097982 -492.423053 -0.023720 -492.348790 Gly-Gly- 0.084609 -491.965780 -0.022514 -491.903685 1 0.216083 -8432.239980 -0.767355 -8432.791252 1a 0.285177 -8771.302257 -0.802060 -8771.819139 1b 0.286586 -8771.289956 -0.805223 -8771.808593 1c 0.298244 -8771.764210 -0.800634 -8772.266600 1d 0.299523 -8771.790225 -0.787344 -8772.278047 2 0.088539 -4216.115639 -0.367328 -4216.394427 2+w 0.107532 -4292.553095 -0.375110 -4292.820673 2+H 0.098098 -4216.555613 -0.368962 -4216.826477 2+Hw 0.121965 -4292.999723 -0.375375 -4293.253133 2a0 0.170987 -4555.659728 -0.395341 -4555.884082 2a 0.190915 -4632.100707 -0.402898 -4632.312690 2a-H 0.178296 -4631.650334 -0.401716 -4631.873753 2b0 0.169687 -4555.652337 -0.407898 -4555.890548 2b 0.191514 -4632.094838 -0.414679 -4632.318002 2b-H 0.179651 -4631.637400 -0.407663 -4631.865412 2b0-H 0.155951 -4555.190579 -0.400560 -4555.435189 2c0 0.168126 -4555.658998 -0.395372 -4555.886244 2c+H 0.202737 -4632.552491 -0.410555 -4632.760309 2c 0.191403 -4632.101993 -0.403730 -4632.314319 2c-H 0.178420 -4631.637543 -0.400406 -4631.859529 2d-bi 0.192474 -4632.106162 -0.401593 -4632.315281 2d 0.197612 -4632.109983 -0.401949 -4632.314320 2d+H 0.203594 -4632.565130 -0.406959 -4632.768495 2d+Hw 0.226070 -4709.008595 -0.413131 -4709.195656 2(a0)2 0.283616 -5047.637267 -0.439170 -5047.792820 2a0d 0.295554 -5048.099255 -0.438949 -5048.242650 2b0d 0.302738 -5048.087700 -0.445222 -5048.230184 2dc+H 0.309322 -5048.543943 -0.450203 -5048.684825 2dd-bi 0.307820 -5048.552102 -0.441656 -5048.685939 2(d+H)2 0.359787 -5201.432059 -0.457196 -5201.529468

a The 𝐺!" values do not include standard state correction.

Table S4. Energy contributions (kcal mol-1) to the relative free energy of the stationary points involved in the first hydrolytic step of water addition to the peptide bond in 2a0d and 2a0d1 complexes of Gly-Gly.

Species ∆𝐸!" ∆ 𝐺! − 𝐸!" ∆∆𝐺!"#$∗ ∆𝐺!"∗ a

M062X M06 BMK M062X M06 BMK G-2a0d - - - - - 0.5b 0.0b 0.3b TS 8.3 11.1 8.3 13.9 5.8 23.7 26.5 23.7 INT -0.9 2.6 -0.9 17.2 9.7 21.7 25.2 21.7 G-2a0d1 - - - - - 0.0b 0.8b 0.0b TS 9.9 12.2 9.0 14.7 4.5 24.8 27.2 24.0 INT 1.3 4.8 1.0 17.7 6.6 21.4 24.9 21.1 a The ∆𝐺!"∗ values include also a standard state correction of -4.3 kcal mol-1. TS and INT energies are calculated with respect to the energy of the corresponding reactant state, either G-2a0d or G-2a0d1. b Relative stability of the reactant complexes calculated with the different functionals.

Gly-Gly hydrolysis via 2a-H path

The presence of an intramolecular OH nucleophile (Zr-OH) and a free ligand -COO- group in the 2a-H species allows for three main mechanisms of nucleophilic attack on the amide carbon atom of Gly-Gly to initiate the process of hydrolysis, referred below as (a), (b) and (c). Mechanism (a) involves a direct intramolecular OH attack while the other two mechanisms involve a nucleophilic attack by a solvent water molecule, assisted by either the ligand -COO- group (b) or the Zr-OH group (c) through proton abstraction from the attacking H2O (general base activity). The corresponding TSs of nucleophilic attack are depicted in Figure S8 and energy data are collected in Table S5.

Figure S8. M062X optimized TS structures corresponding to (a) direct intramolecular OH attack and H2O attack assisted by either (b) the ligand -COO- group or (c) the Zr-OH group in the 2a-H complex. Interatomic distances are in Å and the relative free energy values (in Italics), calculated with the M06 functional, are in kcal mol-1.

Table S5. Energy contributions (kcal mol-1) to the free energy barriers of nucleophilic attack via mechanisms (a), (b) and (c) in the 2a-H complex.

TS ∆𝐸!" ∆ 𝐺! − 𝐸!" ∆∆𝐺!"#$∗ ∆𝐺!"∗

M062X M06 BMK M062X M06 BMK (a) 42.5 41.7 42.8 1.9 -24.8 19.5 18.8 19.9 (b)a 6.8 10.3 7.3 14.1 4.5 21.1 24.6 21.6 (c)a 0.0 2.9 1.4 11.4 16.7 23.8 26.7 25.2 a The ∆𝐺!"∗ values include also a standard state correction of -4.3 kcal mol-1.

As can be expected the intramolecular OH attack (a) has the lowest energy barrier, with a calculated value of 18.8 kcal mol-1. The calculated energy barriers associated with the general base mechanisms involving the ligand -COO- group (b) and the Zr-OH group (c) are 24.6 and 26.7 kcal mol-1, respectively. The higher TS energy of (c) as compared to (b) is in line with the calculated pKa value of the Zr(IV) bound water molecule in 2 (0.6) indicating that the Zr-OH group is less basic than the free ligand -COO- group. Thus, to elucidate the whole process of hydrolysis mechanism (a) was fully investigated. The reaction free energy profile is plotted in Figure S9 while the optimized structures and their relative energies are given in Figure S10 and Table S6, respectively. Intramolecular OH nucleophilic attack on the amide carbon of Gly-Gly (TS1) resulted in a tetrahedral intermediate state where the ligand is tridentate coordinated to Zr(IV) through the amide oxygen, amino nitrogen and the OH oxygen atoms. The free energy of this state is lower than that of TS1 by 4 kcal mol-1. A slightly more stable intermediate (INT2) is obtained after Zr…O(H)C bond rupture to restore the original bidentate coordination. INT1 and INT2 are connected through TS2. The following reaction steps, from INT2 to INT4, correspond to conformational changes, such as OH…OOC hydrogen bond rupture and flipping of the C-N(H)-C “umbrella”, with small energy barriers. TS4 corresponds to a water mediated proton transfer from the OH group to the (former) amide nitrogen thus leading to the formation of an intermediate with four-coordinated nitrogen atom (a direct proton transfer or a proton transfer mediated by two water molecules resulted in significantly higher energy barriers). In the following TS5 this intermediate decomposes to release a Gly anion product. The newly formed anion, however, may interact with the adjacent Zr(IV) center resulting in a complex with two bidentate coordinated Gly ligands (PC). The energy of this complex was found lower than the initial state (2a-H) by 6.4 kcal mol-1. TS4 has the highest energy requirement of 23.8 kcal mol-1 pointing out the proton transfer step as the rate-determining for the whole process of hydrolysis via 2a-H path. The reaction description above involves the stationary points located at the level of optimization, M06-2X functional. It should be noted that according to the M06 functional the RC-TS1-INT1-TS2-INT2 rearrangements should be considered as a one-step process. Also, unlike M06-2X funcitonal M06 and BMK functionals predict TS5 energy lower than that of the preceding INT5 (see Table S6) and thus according to these functionals the proton transfer and the release of a Gly anion will take place in one step.

Figure S9. Free energy profile of the 2a-H path of Gly-Gly hydrolysis obtained with the M06 functional. Free energy values (in Italics) are in kcal mol-1.

Figure S10. M062X optimized geometries of the stationary points along the 2a-H path of Gly-Gly hydrolysis. Interatomic distances are in Å.

Table S6. Energy contributions (kcal mol-1) to the relative free energy of the stationary points along the 2a-H path of hydrolysis.

Species ∆𝐸!" ∆ 𝐺! − 𝐸!" ∆∆𝐺!"#$∗ ∆𝐺!"∗ M062X M06 BMK M062X M06 BMK

2a-H 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 RC 30.1 28.6 29.4 1.3 -29.3 2.1 0.6 1.4 TS1 42.5 41.7 42.8 1.9 -24.8 19.5 18.8 19.9 INT1 28.4 29.9 30.2 2.2 -17.0 13.6 15.1 15.4 TS2 27.7 27.0 29.2 3.8 -16.0 15.5 14.8 17.0 INT2 22.6 22.2 23.8 1.8 -11.6 12.8 12.4 13.9 TS3 14.7 14.3 15.6 0.7 -0.3 15.1 14.8 16.0 INT3 6.3 5.7 7.7 1.2 6.3 13.9 13.3 15.3 INT4 6.8 6.4 7.9 3.3 6.1 16.2 15.8 17.4 TS4a 3.8 5.6 4.9 10.4 12.1 22.0 23.8 23.1 INT5 27.1 25.8 26.3 2.3 -9.4 19.9 18.6 19.2 TS5 32.4 29.2 30.5 1.7 -13.4 20.7 17.5 18.8 PC -1.7 -2.8 -4.3 3.0 -6.6 -5.3 -6.4 -7.8 a The ∆𝐺!"∗ values include also a standard state correction of -4.3 kcal mol-1.

Table S7. Energy contributions (kcal mol-1) to the relative free energy of the stationary points involved in the first hydrolytic step of water addition to the peptide bond in complexes with 2a0d binding mode of Gly-Ala and Gly-Val.

Species ∆𝐸!" ∆ 𝐺! − 𝐸!" ∆∆𝐺!"#$∗ ∆𝐺!"∗ a

M062X M06 BMK M062X M06 BMK A-2a0d1 - - - - - 0.0b 0.0b 0.0b TS 13.4 15.4 12.6 15.0 2.3 26.5 28.5 25.6 V-2a0d1 - - - - - 0.9b 0.2b 0.7b TS 17.1 19.4 15.9 14.1 -0.8 26.1 28.4 24.9 V-2a0d2 - - - - - 0.0b 1.6b 6.4b TS 16.9 17.9 10.8 15.9 3.3 31.9 32.9 25.8 V-2a0d3 - - - - - 1.1b 0.0b 0.0b TS 3.2 6.1 2.2 14.0 15.5 28.5 31.4 27.5 a The ∆𝐺!"∗ values include also a standard state correction of -4.3 kcal mol-1. The TS energies are calculated with respect to the energy of the corresponding initial reactant states. b Relative stability of the reactant complexes calculated with the different functionals.

Figure S11. M062X optimized TS structures of water addition to the amide carbon atom of Gly-Gly, Gly-Ala and Gly-Val. Bond lengths, dihedral angles and M06 activation free energies (in Italics) are in Å, degrees and kcal mol-1, respectively.

Table S8. Energy contributions (kcal mol-1) to the free energy barrier of uncatalyzed hydrolysis of Gly-Gly, Gly-Ala and Gly-Val.

Dipeptide ∆𝐸!" ∆ 𝐺! − 𝐸!" ∆∆𝐺!"#$∗ ∆𝐺!"∗ M062X M06 BMK M062X M06 BMK

Gly-Gly -8.1 -4.9 -6.4 11.1 30.1 28.8 32.0 30.5 Gly-Ala -6.9 -3.5 -4.9 11.1 29.2 29.2 32.6 31.2 Gly-Val -4.3 -0.9 -2.4 11.1 28.1 30.7 34.1 32.6 a The ∆𝐺!"∗ values include also a standard state correction of -4.3 kcal mol-1.

Table S9. Molecular properties of the Gly-X dipeptides calculated with the IEFPCM-B3LYP/6-311+G(2df,2p)//B3LYP/6-311+G(2df,2p) level of theory.

Optimized molecular structures

Quantity Gly-Gly Gly-Ala Gly-Val Gly-Leu Gly-Ile Gly-Phe

Bond length (Å) R(C2-N3) 1.453 1.462 1.462 1.464 1.463 1.458 R(N3-C4) 1.322 1.323 1.323 1.322 1.323 1.324 R(C4-O7) 1.236 1.236 1.237 1.237 1.237 1.235 R(C4-C5) 1.535 1.537 1.537 1.537 1.537 1.535

NBO Charge C2 -0.292 -0.121 -0.114 -0.114 -0.111 -0.109 N3 -0.604 -0.609 -0.607 -0.603 -0.607 -0.609 C4 0.680 0.683 0.682 0.681 0.682 0.682 O7 -0.710 -0.711 -0.711 -0.712 -0.711 -0.709 C5 -0.257 -0.258 -0.258 -0.258 -0.257 -0.257 Hirshfeld charge C2 -0.022 0.017 0.017 0.016 0.017 0.018 N3 -0.064 -0.064 -0.061 -0.061 -0.061 -0.064 C4 0.180 0.182 0.183 0.182 0.183 0.183 O7 -0.323 -0.316 -0.316 -0.317 -0.316 -0.316 C5 0.041 0.040 0.040 0.040 0.040 0.040 AEPa C2 -14.777 -14.770 -14.774 -14.773 -14.774 -14.768 N3 -18.352 -18.358 -18.358 -18.357 -18.358 -18.357 C4 -14.608 -14.610 -14.611 -14.611 -14.611 -14.609 O7 -22.349 -22.350 -22.350 -22.351 -22.350 -22.347 C5 -14.603 -14.607 -14.607 -14.607 -14.607 -14.606 Wiberg bond order C2-N3 0.95 0.94 0.94 0.94 0.94 0.94 N3-C4 1.32 1.33 1.33 1.33 1.33 1.32 C4-O7 1.54 1.53 1.53 1.53 1.53 1.54 C4-C5 0.96 0.96 0.96 0.96 0.96 0.96 PBOb (%) C2-N3 σ(36.79-

63.21) σ(36.68- 63.32)

σ(36.60-63.40)

σ(36.66-63.34)

σ(36.59-63.41)

σ(36.76-63.24)

N3-C4 σ(61.64-38.36)

σ(61.77- 38.23)

σ(61.74-38.26)

σ(61.81-38.19)

σ(61.77-38.23)

σ(61.67-38.33)

C4-O7 σ(35.36-64.64) π(25.83-74.17)

σ(35.30-64.70) π(25.70-74.30)

σ(35.28- 64.72) π(25.70-74.30)

σ(35.32-64.68) π(25.64-74.36)

σ(35.30-64.70) π(25.67-74.33)

σ(35.35-64.65) π(25.93-74.07)

C4-C5 σ(47.98-52.02)

σ(47.92- 52.08)

σ(47.92-52.08)

σ(47.93-52.07)

σ(47.92-52.08)

σ(47.93-52.07)

a Atomic electrostatic potential. b Polarization of the bonding orbitals (from NBO analysis).

CPCM-M062X/LANL2DZ/6-31+G(d,p) optimized geometries of selected species in Cartesian coordinates G-2a0d RC O 1.736757000 0.993745000 -5.013788000 O 2.694419000 4.691851000 -1.022349000 O -2.576980000 3.342544000 -2.358276000 O 2.164254000 2.467308000 -2.656357000 O 0.140786000 3.628553000 -1.414754000 O -0.309354000 1.903935000 -3.337014000 O 2.756113000 -0.109093000 -2.626233000 O 3.300593000 2.016598000 -0.307809000 O 1.331340000 3.169546000 0.928546000 O -1.669908000 2.469948000 0.155617000 O -2.054778000 0.698834000 -1.760793000 O 0.312554000 -0.724602000 -3.285409000 O 4.503712000 -2.321381000 -2.654109000 O 5.483793000 1.373194000 1.362601000 O 1.721664000 3.541808000 3.707290000 O -3.487194000 2.287723000 2.321927000 O -0.045671000 -3.481385000 -3.871120000 O 4.503384000 -0.330003000 -0.645109000 O 2.777716000 1.405234000 2.166984000 O -0.684668000 2.657964000 2.598514000 O -2.706261000 0.125247000 0.769176000 O -1.912006000 -2.021233000 -2.478894000 O 1.770558000 -2.439036000 -1.984412000 O 3.568031000 -2.706053000 -0.034205000 O 3.986850000 -0.943219000 1.862505000 O 0.810496000 0.890260000 3.859979000 O -1.666237000 0.304691000 3.225255000 O -2.472214000 -2.660535000 0.245755000 O -0.378448000 -3.700292000 -1.078913000 O 3.426412000 -3.612552000 2.613134000 O -0.312457000 -1.429586000 4.977002000 O -1.146062000 -4.765065000 1.412191000 O 1.150145000 -3.167065000 1.026032000 O 1.624062000 -1.454327000 2.934433000 O -0.831018000 -2.073862000 2.286043000 O 2.032069000 -0.587397000 0.167328000 O 0.105479000 0.511580000 1.358537000 O -0.368247000 -1.175691000 -0.471245000 O 0.616956000 1.101844000 -1.036553000 P 0.584699000 -0.055763000 -0.004252000 W 1.308274000 0.899864000 -3.377122000 W 1.898748000 3.200157000 -0.897134000 W -1.337496000 2.341055000 -1.734355000 W 3.389385000 -1.594132000 -1.601677000 W 3.999759000 0.703703000 0.888097000 W 1.159295000 2.341710000 2.649954000 W -2.074426000 1.487530000 1.764862000 W -0.135640000 -2.446077000 -2.529004000 W 2.721027000 -2.399527000 1.659748000 W -0.075893000 -0.767467000 3.435391000 W -0.819284000 -3.242591000 0.734458000 Zr -3.032883000 -1.022459000 -1.000081000 C -5.799434000 -2.046044000 0.036844000 O -4.999411000 -1.069432000 0.084528000 C -5.343460000 -3.319859000 -0.635891000 H -4.837274000 -3.921518000 0.125324000 N -4.369404000 -2.945673000 -1.661822000 H -3.726803000 -3.709790000 -1.853566000 H -6.192346000 -3.886328000 -1.027738000 H -4.857503000 -2.697393000 -2.522373000 C -8.968265000 -1.031960000 1.668154000 O -9.456135000 -2.155706000 1.386245000

O -9.523538000 -0.072157000 2.248058000 C -7.499539000 -0.794497000 1.255197000 H -7.434833000 0.071203000 0.586975000 N -6.986777000 -1.979788000 0.589729000 H -6.904146000 -0.568520000 2.145556000 H -7.655095000 -2.746294000 0.532039000 O -6.704720000 2.509157000 0.037291000 C -4.713110000 3.816292000 -0.139310000 H -3.685845000 3.448713000 -0.102508000 N -5.131115000 4.212953000 1.229664000 H -4.908642000 5.187613000 1.437450000 H -4.759415000 4.684675000 -0.797486000 H -6.144369000 4.058970000 1.321537000 C -5.687372000 -0.186552000 -2.529665000 O -4.399340000 -0.251299000 -2.491615000 O -6.446008000 -1.144324000 -2.677519000 C -6.269676000 1.223313000 -2.433615000 H -6.495206000 1.555899000 -3.452924000 N -5.384176000 2.174878000 -1.792832000 H -4.497779000 2.410573000 -2.234228000 H -7.204324000 1.187762000 -1.873531000 C -5.692046000 2.748599000 -0.623894000 H -4.651208000 3.604078000 1.916214000 G-2a0d TS O -1.806905000 4.419885000 2.526099000 O -3.118592000 3.663101000 -2.786319000 O 2.237413000 4.179710000 -1.288313000 O -2.366986000 3.532203000 -0.069490000 O -0.483426000 3.447832000 -1.914442000 O 0.153956000 3.832915000 0.606011000 O -2.693962000 1.816406000 1.943583000 O -3.471497000 1.389867000 -1.114090000 O -1.653263000 1.264772000 -2.966692000 O 1.396725000 1.622516000 -2.187765000 O 2.060822000 1.960851000 0.336605000 O -0.179561000 2.099666000 2.606526000 O -4.172396000 0.295361000 3.827283000 O -5.614057000 -0.390440000 -1.481662000 O -2.130137000 -0.683854000 -4.972606000 O 3.207371000 -0.006438000 -3.609314000 O 0.505500000 0.862337000 5.051133000 O -4.421504000 0.069417000 1.009855000 O -2.931406000 -0.884771000 -2.265690000 O 0.371437000 -0.220123000 -3.812375000 O 2.669735000 -0.288272000 -0.913399000 O 2.178883000 0.771804000 2.876496000 O -1.456603000 -0.076185000 3.239795000 O -3.247551000 -1.875169000 2.325053000 O -3.889026000 -2.208424000 -0.195642000 O -0.924452000 -2.411594000 -3.127141000 O 1.615062000 -2.125388000 -2.510354000 O 2.721400000 -1.730808000 1.641105000 O 0.776510000 -1.445616000 3.443729000 O -3.067815000 -4.474865000 1.254942000 O 0.483443000 -4.656594000 -2.174727000 O 1.561662000 -4.018592000 2.626177000 O -0.839941000 -2.826665000 1.805993000 O -1.469145000 -3.226216000 -0.698322000 O 1.024097000 -2.981434000 0.011026000 O -1.948692000 -0.576227000 0.459581000 O -0.159290000 -0.675458000 -1.309441000 O 0.505215000 -0.327818000 1.110940000 O -0.697397000 1.508701000 -0.175193000 P -0.560965000 -0.022330000 0.039428000 W -1.391287000 3.122551000 1.518618000 W -2.168683000 2.667360000 -1.796616000

W 1.129065000 2.965209000 -0.806803000 W -3.151534000 0.017509000 2.500404000 W -4.061401000 -0.374941000 -0.799263000 W -1.434983000 -0.600260000 -3.428497000 W 1.881311000 -0.186666000 -2.532881000 W 0.463522000 0.477283000 3.397915000 W -2.480001000 -2.928625000 0.880216000 W 0.190361000 -3.064159000 -1.675734000 W 1.090295000 -2.547842000 1.922184000 Zr 3.199668000 0.261988000 1.072867000 C 5.910286000 -1.202400000 1.103116000 O 4.988770000 -0.718522000 0.317077000 C 6.075581000 -0.470649000 2.424369000 H 6.679427000 -1.045735000 3.131016000 N 4.728156000 -0.173563000 2.918537000 H 4.365609000 -0.923727000 3.503517000 H 6.575835000 0.477482000 2.209689000 H 4.741728000 0.687565000 3.466250000 C 6.602014000 -3.542205000 -1.065772000 O 5.965366000 -4.119696000 -0.111699000 O 6.847297000 -4.065414000 -2.160156000 C 7.086333000 -2.095371000 -0.862504000 H 8.095150000 -2.027552000 -1.275104000 N 7.100588000 -1.571036000 0.490744000 H 6.442768000 -1.453451000 -1.469980000 H 7.771422000 -2.004562000 1.113852000 O 6.653720000 2.433595000 -1.078699000 C 4.671185000 2.640156000 -2.393356000 H 3.808566000 2.102156000 -1.992891000 N 5.412562000 1.718254000 -3.290805000 H 5.787215000 2.193932000 -4.114030000 H 4.311397000 3.505674000 -2.948593000 H 6.211226000 1.339554000 -2.758186000 C 5.172363000 2.826055000 1.789780000 O 4.561929000 1.910338000 1.135323000 O 5.442465000 2.794146000 2.992057000 C 5.598391000 4.040531000 0.946190000 H 5.222897000 4.947933000 1.421276000 N 5.100825000 3.967630000 -0.412268000 H 4.137527000 4.256314000 -0.576013000 H 6.689811000 4.088031000 0.941458000 C 5.581543000 3.016547000 -1.229980000 H 4.791337000 0.949066000 -3.598576000 O 5.246278000 -2.693847000 1.700258000 H 5.559081000 -3.385811000 0.883625000 H 4.270831000 -2.561363000 1.671006000 G-2a0d INT O -1.813551000 4.519663000 2.335508000 O -3.156737000 3.530245000 -2.926657000 O 2.211939000 4.116053000 -1.486005000 O -2.386603000 3.515636000 -0.214755000 O -0.515193000 3.357278000 -2.066409000 O 0.139163000 3.852200000 0.431062000 O -2.700596000 1.891344000 1.866342000 O -3.490944000 1.327376000 -1.158002000 O -1.685089000 1.128650000 -3.018329000 O 1.363864000 1.522307000 -2.273235000 O 2.050726000 1.966296000 0.224287000 O -0.183748000 2.209703000 2.509657000 O -4.163502000 0.459588000 3.826774000 O -5.627782000 -0.480441000 -1.439366000 O -2.165307000 -0.911166000 -4.931481000 O 3.181810000 -0.160547000 -3.619964000 O 0.520111000 1.074136000 5.001986000 O -4.430909000 0.096325000 1.025473000 O -2.948658000 -0.993960000 -2.212079000

O 0.339918000 -0.392871000 -3.807268000 O 2.653282000 -0.327636000 -0.916698000 O 2.182575000 0.902806000 2.826852000 O -1.452687000 0.059437000 3.242146000 O -3.242641000 -1.781338000 2.421153000 O -3.892201000 -2.230864000 -0.080468000 O -0.948616000 -2.553810000 -3.017365000 O 1.593515000 -2.235627000 -2.429228000 O 2.730549000 -1.641591000 1.701036000 O 0.789923000 -1.294025000 3.496356000 O -3.053307000 -4.424042000 1.475015000 O 0.466883000 -4.752044000 -1.969150000 O 1.583236000 -3.892341000 2.779087000 O -0.829894000 -2.744633000 1.928981000 O -1.473237000 -3.258861000 -0.548287000 O 1.026862000 -2.975010000 0.129256000 O -1.963539000 -0.560306000 0.487343000 O -0.176473000 -0.737306000 -1.280403000 O 0.488033000 -0.284971000 1.123716000 O -0.712457000 1.493768000 -0.244654000 P -0.575567000 -0.026056000 0.040352000 W -1.396455000 3.180509000 1.383614000 W -2.196206000 2.578126000 -1.903430000 W 1.108349000 2.920021000 -0.948877000 W -3.147790000 0.122639000 2.508737000 W -4.072227000 -0.425835000 -0.763505000 W -1.459411000 -0.754636000 -3.397317000 W 1.860996000 -0.300316000 -2.528901000 W 0.477045000 0.620672000 3.364597000 W -2.475314000 -2.892871000 1.026996000 W 0.172804000 -3.137664000 -1.544561000 W 1.107698000 -2.453116000 2.013822000 Zr 3.241456000 0.326400000 1.045052000 C 5.872409000 -1.229659000 1.187586000 O 4.987387000 -0.634881000 0.350471000 C 6.080698000 -0.372009000 2.436992000 H 6.690070000 -0.891367000 3.183913000 N 4.740558000 -0.028438000 2.929873000 H 4.370678000 -0.738692000 3.558375000 H 6.579858000 0.552256000 2.138488000 H 4.768927000 0.860303000 3.430648000 C 6.896813000 -3.528242000 -0.987291000 O 6.208145000 -4.178682000 -0.066479000 O 7.333664000 -4.104922000 -1.968153000 C 7.114264000 -2.024011000 -0.805371000 H 8.055445000 -1.793722000 -1.310070000 N 7.133562000 -1.478692000 0.537671000 H 6.314182000 -1.520496000 -1.358058000 H 7.790539000 -1.947723000 1.153372000 O 6.652466000 2.432189000 -1.150128000 C 4.642045000 2.511840000 -2.434681000 H 3.810825000 1.968826000 -1.977866000 N 5.388938000 1.562574000 -3.297676000 H 5.772808000 2.014460000 -4.130193000 H 4.234390000 3.328087000 -3.029923000 H 6.182457000 1.196872000 -2.750147000 C 5.190497000 2.963909000 1.712801000 O 4.520604000 2.042564000 1.133729000 O 5.521278000 2.978847000 2.900695000 C 5.597884000 4.131029000 0.793748000 H 5.220857000 5.062030000 1.219922000 N 5.081946000 3.975305000 -0.551785000 H 4.110960000 4.235654000 -0.717221000 H 6.688320000 4.186708000 0.769969000 C 5.566609000 2.984514000 -1.318904000 H 4.766098000 0.788066000 -3.590790000 O 5.315908000 -2.512133000 1.636353000 H 5.830428000 -3.556465000 0.642746000 H 4.338691000 -2.405776000 1.666926000

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