General AMBER Force Field Parameters for Diphenyl Diselenides and

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General AMBER Force Field Parameters for Diphenyldiselenides and Diphenylditellurides Mauro Torsello, Antonio Cesar Pimenta, Lando Peter Wolters, Irina Sousa Moreira, Laura Orian, and Antonino Polimeno J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b02250 • Publication Date (Web): 07 Jun 2016 Downloaded from http://pubs.acs.org on June 11, 2016

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The Journal of Physical Chemistry

General AMBER Force Field Parameters for Diphenyldiselenides and Diphenylditellurides Mauro Torsello,a Antonio C. Pimenta,b Lando P. Wolters,a Irina S. Moreira,b Laura Oriana* and Antonino Polimenoa a

Dipartimento di Scienze Chimiche Università degli Studi di Padova, Via Marzolo 1 35131 Padova Italy b

CNC—Center for Neuroscience and Cell Biology, Universidade de Coimbra, Rua Larga, FMUC, Polo I, 1°andar, 3004-517 Coimbra, Portugal

ABSTRACT: The General AMBER Force Field (GAFF) has been extended to describe a series of selenium and tellurium diphenyldichalcogenides. These compounds, besides being eco-friendly catalysts for numerous oxidations in organic chemistry, display peroxidase activity, i.e. can reduce hydrogen peroxide and harmful organic hydroperoxides to water/alcohols and as such are very promising antioxidant drugs. The novel GAFF parameters are tested in MD simulations in different solvents and the

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Se NMR chemical shift of diphenyldiselenide is computed using structures

extracted from MD snapshots and found in nice agreement with the measured value in CDCl3. The whole computational protocol is described in detail and integrated with inhouse code to allow easy derivation of the force field parameters for analogous compounds as well as for Se/Te organocompounds in general.

INTRODUCTION Organoselenium compounds are important catalysts in organic chemistry,1,2 with promising application in green chemistry,3,4 but are also intensively studied for their potential use as therapeutic agents.5,6 Selenium is a bioessential element and is present in 25 selenoproteins in the form of selenocysteine (Sec), the 21st aminoacid. The presence of Sec, typically ascribed to its superior 1 ACS Paragon Plus Environment


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nucleophilicity, superior leaving group and electron acceptor ability relative to Cys, is still under debate.7 The specific role of selenium rather than sulfur is particularly intriguing in the family of glutathione peroxidase (GPx) enzymes. The biological function of these enzymes is crucial in signalling pathways, but is especially fundamental in the reduction of hydrogen peroxide and harmful organic hydroperoxides to water and alcohols, respectively.8,9 The overall reaction (Scheme 1) requires two equivalents of glutathione (GSH) as cofactor and involves three main steps, i.e. (i) oxidation of the selenol (ESeH) to selenenic acid (ESeOH), accompanied by the reduction of the hydroperoxide and the release of one water/alcohol molecule; (ii) reaction of ESeOH with a glutathione (GSH) to form a selenenylsulfide intermediate (ESeSG) and release of a water molecule; (iii) regeneration of the initial selenol ESeH upon reaction with the second GSH accompanied by the formation of a disulfide product (GSSG).10-14

Scheme 1. Mechanism of organic hydroperoxide reduction catalyzed by GPx (ESeH). It is well known that upon replacement of Sec with Cys, i.e. of selenium with sulfur, the enzymatic activity is reduced by several orders of magnitude, a phenomenon which might explain

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why in nature selenium has survived in the catalytic site of GPx, despite that a complex and energetically very expensive cotranslational insertion machinery is required for Sec.15,16 The biological importance of GPx has pushed the research in the last few decades to the design of organoselenium compounds that might be used in medicine as GPx mimics, maintaining in particular the peroxidaselike antioxidant activity, but also antitumor and antimicrobial properties.17,18 Among the synthetic small organoselenium compounds which mimic the properties of GPx, ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is well known also for its antiinflammatory, antiatherosclerotic and cytoprotective properties observed in both in vitro and in vivo models.19 Ebselen was synthesized in 192420 but its antioxidant properties were discovered only in 1984:21,22 since then it is undoubtedly the most studied GPx mimic.23-26 The organoselenium synthetic GPx mimics reported in literature have been conveniently classified by Mugesh and Bhabak17,18 in three major categories: (i) cyclic selenenyl amides having a Se-N bond; ebselen belongs to this category; (ii) diphenyldiselenides and (iii) aromatic or aliphatic monoselenides. Our interest is mainly on diphenyldiselenides, and more in general on diphenyldichalcogenides (Scheme 2), for the presence of a chalcogenchalcogen bond, as well as for their peroxidaselike efficiency, the mechanistic details of which are not clear yet.27-29



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Scheme 2. Diphenyldichalcogenides included in the present work. Differently from selenium, tellurium has not any known biological function and is in general believed to be more toxic than selenium.6 Also, Te compounds, whose pharmacological effects are less known, possess strong peroxidase activity, as first claimed by Andersson and coworkers.30 Subsequently Engman31 reported on diarylditellurides and very recently Rocha et al.32,33 presented several experimental studies on the antioxidant activity of diphenylditellurides. In addition, Te compounds have been investigated as chemopreventive agents and diphenylditelluride appears to have a very high capacity of inducing apoptotic cell death.27,33 Importantly, the toxicity of organotellurides is found to be comparable to organoselenides and this paves the route to their possible use as drugs, in particular as antioxidant GPx mimics, although careful control is warmly recommended.27,33 From a mechanistic point of view, small organoselenium compounds show some limitations and often their catalytic activity is relatively poor.24 On the basis of the available experimental and computational studies this can be ascribed to (i) a competing undesired thiol exchange reaction which hampers the regeneration of the selenol,34 due to the fact that nucleophilic attack at Se (reaction III, Scheme 1) is both thermodynamically and kinetically favored;35,36 (ii) the nature of the thiol cosubstrate, which may have a dramatic effect on the catalytic activity of ebselen and its analogues;3740

(iii) the nonspecificity for the substrate which leads to undesirable reactions with Cys residues in

different protein sites. Mechanistic studies on organotellurium compounds and their GPx activity are still scarce; nevertheless the experimental evidence on diphenylditellurides reported very recently by Rocha et al. is undoubtedly attractive.27,33 Aiming at an accurate drug design through in silico methodologies adopting a bottomup approach, a quantum chemical mechanistic investigation of the single molecule is a fundamental starting point to disclose in detail the intimate connection between the atomistic nature of the compound and its 4 ACS Paragon Plus Environment

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reactivity. For example, referring to the systems here discussed, accurate quantum mechanics studies have shed some light on the difference between sulfur and selenium in the reaction of hydroperoxide reduction by model thiols/selenols41,42 or in the reactions of thiolate nucleophilic attack to homo/hetero dichalcogenides containing sulfur as well as selenium.35,43-45 Numerous density functional theory (DFT) contributions can be found on the reactivity of ebselen.46-48 Combined experimental and DFT studies allowed to identify suitable molecular features which enhance the peroxidase activity of amine based diphenyldiselenides.49 At this point, the next step in drug design requires the docking of the molecule in a biological environment, but simulations of these drugs in contact with biomolecules or testing their reactivity once they are bioincorporated in a suitable protein scaffold is a challenging goal, which requires molecular dynamics (MD) techniques as well as hybrid quantum mechanics and molecular mechanics (QM/MM) approaches. The lack of parameters in the available force fields (e.g. force constants, equilibrium bond lengths and angles, torsions, charges) for diphenyldiselenides and diphenylditellurides, and more generally for Se and Te compounds, prompted us to derive them, setting up a computational protocol based on the most recent tools. Besides docking and bioincorporation, the availability of force field parameters for this class of compounds will allow, for example, mechanistic investigation of the GPx mimic activity and, more in general, of dichalcogenides catalytic activity in organic reactions of interest in a complex environment through QM/MM approach.

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Se and

125

Te NMR calculations might be carried out in

silico for structural investigation in solution. In addition, due to their inherent chirality deriving from their two helical enantiomeric conformations, which arises from their skewed arrangement, the different stabilization of diphenyldichalcogenides in chiral environments is exploited in circular dichroism; also in this case the incorporation of diphenyldichalcogenides in a complex environment might be useful to study Cotton effect in silico.50 The Assisted Model Building with Energy Refinement (AMBER) Hamiltonian has been chosen, due to its large success in the simulation of biomolecules, proteins and nucleic acids.51 The AMBER potential has the form: 5 ACS Paragon Plus Environment


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𝑛′𝑎𝑡𝑜𝑚𝑠

𝑉𝐴𝑀𝐵𝐸𝑅

𝑛′𝑎𝑡𝑜𝑚𝑠

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𝑞𝑖 𝑞𝑗 𝜎𝑖𝑗 = ∑ + ∑ 4𝜀𝑖𝑗 [( ) 4𝜋𝜀0 𝑟𝑖𝑗 𝑟𝑖𝑗 𝑖 CH3 ~ Cl > H > NO2 (Figure 2 and Table 2), which follows qualitatively the Hammett series (with the exception of Cl that should fall between H and NO2) for substituents in para position. Indeed the more negative σpara is, the stronger electron donor the substituent is and this leads to a higher rotational barrier, e.g. in the case of the amino group, reaching at maximum about 2.6 Kcal/mol and 2.1 Kcal/mol for the Se and Te compounds respectively. Tellurium derivatives have a slightly lower rotational barrier. In the case of


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the para-nitro compounds there is also a shift of the PES along the abscissa by 90°, because, differently from the others, these molecules are more stable in the closed conformation. It is noteworthy that the motion of rotation of the phenyl rings about their axes in diphenyldichalcogenides was studied about 40 years ago by measuring the spin-lattice relaxation times (T1) of

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C.73 Using a rigid anisotropic model with  set equal to 90°, the tumbling of the

phenyl rings was investigated and found to be less and less hindered when going from S to Se and Te, a result which is in agreement with our findings on the energetics of these compounds. Instead, for the  dihedrals, a preliminary inspection carried out at the B3LYP/SDD,6311G(d,p) level of theory did not show any significant difference due to the substituent (Figure S1); thus the PES for rotation of the  dihedral computed at B3LYP/cc-pVTZ(-PP) level of theory for the two parent compounds is employed for the substituted derivatives too. The height of the  rotational barriers for the parent compounds is approximately one order of magnitude higher than for the Φ dihedral.

Figure 2. Energy profiles at B3LYP/cc-pVTZ(-PP) level of theory for the rotation of Φ of all Se (a) and Te (b) diphenyl compounds.



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Table 2. Torsional barriers related to  and Hammett  constants for substituents in para position; values for Te compounds are given in parentheses. Substituent

NH2

OCH3

CH3

Cl

H

NO2

Barrier height (Kcal mol-1)

2.6

2.2

1.3

1.2

0.9

0.8

(2.1)

(1.8)

(1.1)

(1.1)

(0.9)

(0.4)

σpara

-0.66

-0.27

-0.17

+0.23

0.00

+0.78

To obtain the missing parameters in GAFF, i.e. the charges and the LennardJones constants, as well as the parameters required to describe the stretching, bending and torsional contributions to the potential involving at least one chalcogen atom, the following procedures were carried out.

Atom charges and LennardJones parameters. The atom charges were first computed for all the optimized geometries of multiple conformers, at HF/6-31G(d),cc-pVTZ(-PP) level, fitting the electrostatic surface potential (ESP) using the electrostatic charge computing method by Merz and Kollman.62 This QM level of theory was chosen to be consistent with previous parametrization;52 exceptionally, since the 6-31G(d) basis set is not available for Te, we have employed cc-pVTZ(-PP)74 for Te and Se as well. First of all the number of layers and grid points for the electrostatic potential fitting has been investigated for Se and Te derivatives. Increasing by 10 the number of layers and grid points beyond the recommended values (10 and 17, respectively), did not produce relevant difference in the charges and dipole moments of the parent compounds, the latter changing by less than 1%. Multiconformation effects were taken into account to obtain more robust partial charges using two conformations (open and closed) for the parent as well as for all substituted compounds. Atomcentered partial charges were then derived according to the RESP methodology outlined by Kollman et al.62 In Figure 3, the electrostatic surface potential and the RESP charges of the parent compounds are shown; the RESP charge values for all compounds are listed in Table 3. Constraints were used during the fitting, so that chemically equivalent atoms have the same charge. The charges on the chalcogens become approximately less negative when going from the strongest electron donor 14 ACS Paragon Plus Environment

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to the strongest electron withdrawing group in the series. We have also taken into account multiorientation effects, as proposed by some authors, since the presence of big atoms, in our case of the chalcogens, can make the calculation of the charges of the close buried atoms unstable.63-65 Indeed this was mandatory for (p-Cl-X)2 and allowed to minimize the otherwise unphysical large charges of C1 and CX, but was found negligible for the parent compounds.

Figure 3. Parent compounds: electrostatic surface potential and RESP charges of (PhSe)2 (a and b) and (PhTe)2 (c and d); the global minimum geometry is used for the representation.



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Table 3. RESP charges; values for Te compounds are given in parentheses. X (p-NH2-PhX)2

(p-OCH3-PhX)2

-0.140095 (-0.100312)

-0.122505 (-0.084124)

Cx

-0.119705 (0.035058)

0.036504 (-0.025935)

C1(=C5)

-0.142116 (-0.090951)

-0.072294 (-0.050396)

C2(=C4)

-0.356906 (-0.386461)

-0.399946 (-0.408257)

C3

0.473450 (0.492143)

0.530932 (0.543914)

H1(=H4)

0.160820 (0.147236)

0.152239 (0.147382)

H2(=H3)

0.190714 (0.194704)

0.190539 (0.189615)

R(=R') N

H

-0.910606 (-0.903764)

0.376261 (0.373910)

O

C

H

-0.396038 (-0.411340)

-0.015674 (0.004244)

0.075235 (0.072184)

C

H 0.119183 (0.121638)

(p-CH3-PhX)2

-0.121651 (-0.079513)

-0.113947 (0.027097)

-0.137652 (-0.088486)

-0.323703 (-0.353883)

0.329828 (0.359165)

0.155804 (0.143699)

0.178847 (0.181825)

-0.426264 (-0.437973)

(p-Cl-PhX)2

-0.086523 (-0.040371)

0.077610 (-0.007854)

-0.150530 (-0.116327)

-0.087459 (-0.088211)

-0.002068 (0.002164)

0.152655 (0.141329)

0.144633 (0.141390)

-0.107617 (-0.110301)

(PhX)2

-0.115244 (-0.073755)

0.133007 (0.056209)

-0.148740 (-0.106937)

-0.156617 (-0.183825)

-0.130699 (-0.105684)

0.141678 (0.130557)

0.148814 (0.152151)

0.142666 (0.139338) N

O

(p-NO2-PhX)2

-0.059245 (-0.008853)

0.082713 (-0.013892)

-0.115092 (-0.059956)

-0.220180 (-0.255448)

0.114185 (0.149797)

0.151408 (0.137494)

0.200601 (0.203458)

0.701682 (0.690059)

-0.436404 (-0.434104)

Cl

The  and  values of the LJ term employed in this work are 2.1200 Å and 0.2910 Kcal mol1

for Se, and 2.2600 Å and 0.3980 Kcal mol-1 for Te, respectively.75 For the other atoms we kept the

GAFF parameters. The cross terms were obtained using the Lorentz/Berthelot mixing rules, i.e. 𝜎𝑖𝑗 = 0.5(𝜎𝑖𝑖 + 𝜎𝑗𝑗 ) and 𝜀𝑖𝑗 = √𝜀𝑖𝑖 ∙ 𝜀𝑗𝑗 .

Parametrization of the harmonic contributions. As stated above, in agreement with the AMBER philosophy, the stretching and bending parameters have been determined only for the parent compounds and transferred to all twelve molecules reducing the number of the new atomtypes. The first harmonic term in the AMBER potential (Eq. 1) represents the stretching of the bonds. Constrained scans, i.e. keeping all other degrees of freedom frozen, were performed starting from the optimized geometry and elongating the CXX and the XX’ bonds in 20 steps of 0.02 Å increments. These curves were truncated at the point at which the energy had increased roughly 5 Kcal mol–1. The selected points (11 to 12 for CXX bonds, and 13 to 17 for XX’) were fitted using a quadratic 16 ACS Paragon Plus Environment

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polynomial, yielding by construction a value of req corresponding to the actual optimized equilibrium geometry. The same procedure was adopted for the CXXX’ and C1CXX angles to parametrize the second harmonic term representing the bending of the angles; the corresponding equilibrium value for θeq was used in this case. For the CXXX’ angles, datapoints within 5 Kcal mol–1 of the equilibrium value were selected (resulting in 9 to 13 points), whereas for the more rigid C1CXX angles the threshold was raised to 20 kcal mol–1 in order to have sufficient datapoints (10 to 12). The parameters obtained for the parent compounds are listed in Table 4. When going from Se to Te the stretching force constants become smaller, due to the weakening of the chalcogenchalcogen and carbonchalcogen bonds. This trend is in agreement with the force constants of the analogous SS (𝑟𝑒𝑞 =2.050 Å; 𝑏=161.7 Kcal mol-1 Å-2) and C (aromatic)S (𝑟𝑒𝑞 =1.770 Å; 𝑏=256.6 Kcal mol-1 Å-2) bonds already present in GAFF, which have the largest force constants. Table 4. Forcefield parameters for the parent compounds; values for Te compounds are given in parentheses. GAFF atomtypes nomenclature is used: CX=ca, H=ha; for sake of completeness all GAFF parameters for these molecules are given.a This is the factor which divides the barriers. b New parameters (PhX)2 Bonds req

Angles B

θeq

a

xx 2.330 109.0 (2.743) (71.6)

xxca 104.53 67.13 (100.92) (40.47)

xca b

xcaca b

b

IDIVF

a

V1/2

Dihedrals V2/2 V3/2

V4/2

γ

-1.8498 (-1.4681)

caxxca -1.6208 -0.6648 (-2.7095) (-0.5895)

0.0015 (0.0168)

180

0.0679 (0.0650)

180



180

b

1.948 143.4 124.14 (2.145) (122.8) (119.94)

86.16 (78.24)

caca 1.387 478.4

cacaca 119.97 67.18

caha 1.087 344.3

cacaha 120.01 48.46

b

1

xxcaca b 1

2.5629 (0.2825)

0.2734 (0.0821)

0.8091 (-0.0954)

x/cacacaca 4



x/ca/hacacaha 14.5 



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Parametrization of the torsional contributions. After deriving the charges and the parameters of the harmonic contributions, the determination of the parameters for the Ψ and Φ dihedrals was left. The torsional term of Eq. 1 must be obtained considering the difference between the quantum mechanics PES and the molecular mechanics PES computed using the complete potential without the torsional contribution. In fact, this last term is the correction to the molecular mechanics PES that will allow reproducing the accurate quantum potential. Given the preliminary finding that the Ψ rotation PES did not show significant differences (Figure S1) when varying the substituent in para position, we calculated the potential only for the parent compounds. Conversely, Φ was computed for each molecule, that is all the bonded FF parameters obtained for diphenyldiselenide and diphenylditelluride have been transferred to the other molecules except for the Φ dihedral. In order to obtain the quantum PES, relaxed scans were run separately for rotation around the Ψ and Φ dihedrals starting from the global minima; the rotation was done increasing each dihedral separately with 35 steps of 10°. All the energies and structures were calculated at B3LYP/cc-pVTZ(-PP) level of theory. Afterwards, they were extracted from the Gaussian output file and converted to a suitable format (i.e. .dat and .mdcrd files) manageable with the Paramfit suite,54 using an inhouse C++ program (provided in the SI). For all the molecules the Fourier expansion was truncated to the fourth term, in order to get a reasonably low value of the least square sum (less than 1 Kcal mol-1), which did not improve further by adding extra terms. The Vi,n parameters were optimized, while setting all the γ phases equal to 180°, because their optimization was not necessary; this strategy allowed to keep a low number of free parameters. The fitting of the quantum PES is very good; the conformational space sampling of the parent compounds based on the QM scans, which can be inspected in Figure 4, is of high quality.


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Figure 4. Conformational space sampling based on the QM scans of (PhSe)2 (a) and (PhTe)2 (b).

Based on AMBER philosophy, the parameters of Table 4 are valid for the class of compounds here described. In any case, due to the low barriers associated to the rotation of the phenyls about their axes, for an accurate description we recommend to use the parameters reported in Tables S1-S5, which have been derived taking into account the dependence of the energy profile upon Φ for all the different substituted dichalcogenides.

Testing the novel GAFF parameters. Unluckily there are no thermodynamic data available for these molecules to validate the derived force field parameters, mainly because these compounds are used in in vitro/in vivo tests or catalytic processes. Firstly we calculated the molecular dipole moment from the optimized MM models. We compared the electrostatic dipole moment of all twelve diphenyl derivatives calculated using (A) the ab initio density and dipole integrals computed at HF/631G(d),cc-pVTZ(-PP) level with the B3LYP/cc-pVTZ(-PP) optimized structures to (B) the values obtained using RESP atom-centered point charges and the MM optimized molecular structure 19 ACS Paragon Plus Environment


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(minimization of a single molecule in vacuo); the results are shown in Table S7. The dipole moments of the open/closed conformers show an average difference of 0.6 Debye (diselenides) and 0.8 Debye (ditellurides). By comparing the MM and QM dipole moments of closed conformers an average difference of 0.3 Debye is found for diselenides as well as for ditellurides, with the highest discrepancy for (p-NH2-PhTe)2 (0.66 Debye). These differences decrease to 0.16 and 0.2 Debye if the average values of the QM dipole moments of the two conformers are considered, with the highest discrepancy still found for (p-NH2-PhTe)2 (0.57 Debye). Taking into account that the QM value necessarily refers to a single conformer, while MM value is calculated for the closed conformer but the RESP charges were obtained by a multiconfigurational fit, we consider these discrepancies acceptable. Important, the agreement improves even further when the MM value is obtained using the RESP charges fitted for only the closed conformation. We tested our extension of GAFF by performing four MD simulations of the parent compounds in two different solvents, i.e. chloroform66 and TIP3P water.67 In each simulation a single molecule in a box was considered in order to avoid the formation of aggregates that may lead to unbalanced distributions. The MD simulation was carried out for 500 ns. The XX bond length is very well maintained in the two different solvents with the average values falling at 2.33 Å and 2.74 Å for (PhSe)2 and for (PhTe)2, respectively. The same holds for the CX-X/ CX’-X’ bonds and CXXX’/CX’X’X angles, the average values of which are equal to 1.95 Å and 105°, for (PhSe)2, and to 2.14 Å and 102°, for (PhTe)2. From the analysis of the trajectories it emerges that Ψ values fall at ±90° for both parent compounds in both solvents (Figure 5 and Figure S2). The Φ values exhibit very similar distributions for both compounds in chloroform (Figure 6), where the closed conformer is more easily found (peaks at 0°,±180°). Instead, using TIP3P water, we find that (PhSe)2 has the same behaviour, while (PhTe)2 surprisingly assumes more frequently the open conformation (peaks at ±90°). These results, in agreement with the crystallographic data (Table 1), were not found using


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the QM calculations in vacuo and highlight that the stabilization due to the medium is a very important ingredient to be taken into account when involved energies are in the order of few Kcal mol-1.

Figure 5 Trajectories (a and c) and distributions/QM PES (b and d) of Ψ in water for (PhSe)2 (a and b) and (PhTe)2 (c and d); the vertical axis on the left is used for the distributions and the vertical axis on the right is used for the energies (b and d).



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Figure 6. Distributions of  in chloroform and water for (PhSe)2 (a, b) and (PhTe)2 (c, d).

In order to get more insight on the results of (PhSe)2, we have computed the 77Se NMR chemical shift combining DFT calculations and MD simulations. 1250 structures were extracted from the MD trajectory in chloroform. The distribution of  is very similar to that of Figure 6a, only slightly more noisy (Figure S3). The chemical shifts were computed at B3LYP/cc-PVTZ in chloroform. It is worth to note that the values for the two conformers are significantly different, i.e. 644 ppm (open) and 462 ppm (closed). The measured value in chloroform is 463 ppm, very close to the value computed for the closed conformer, but this agreement seems fortuitous, since the easy tumbling of the phenyls in solution leads to interconversion between the open and closed conformers, as assessed also in literature.73 The average chemical shifts computed for the 1250 structures extracted from the MD trajectory in chloroform was 507 ppm. Taking into account that (i) no attempt of refining the QM 22 ACS Paragon Plus Environment

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level of theory used to compute the shielding constants was done, (ii) no explicit solvent molecules have been included in the QM calculations to take into account the direct effect of the solvent,76 (iii) the chemical shift range of this nucleus is large, spanning approximately 3000 ppm and (iv) the reported error for these calculations is 30-70 ppm,77,78 and the large sensitivity of 77Se NMR chemical shift to the orientation of the aryl groups,79 we can conclude that our result reflects the preference for the closed conformation in solution and is indeed in agreement with the measured value.

CONCLUSIONS We have extended the popular GAFF to a series of diphenyldiselenides/ditellurides. Besides the well known use in organic catalysis of Se compounds, recently evaluated also in green reactions, this class of Se and Te compounds has significant antioxidant peroxidase activity, and some of them also have efficient antitumor and antimicrobial properties. The intrinsic symmetry, the presence of the chalcogenchalcogen bond and the aromatic rings with different para-substituents make these compounds and their chemistry intriguing. As quantum chemistry level of theory we chose B3LYP/cc-pVTZ(-PP) which offers good geometry accuracy at an affordable computational cost. Based on QM calculations we proved that (i) the barrier associated to the rotation of the phenyl rings about their axis is small, and that (ii) this barrier is affected by changes in the electrondonating/withdrawing character of the para substituents, the trend reflecting quite well the Hammett series. MD simulations in chloroform and water show that the main structural features of the parent Se and Te compounds are conserved in presence of explicit solvent. From the trajectories frequent jumps between the two more stable conformers ( roughly ±90º), are observed, as expected from the values of the lowest interconversion barrier (about 5 Kcal mol-1). This is drawn by the two peak distribution of , barely different for (PhSe)2 and (PhTe)2. In contrast, the distributions of  are less sharp and the closed conformer is more frequently found in chloroform. Importantly, upon switching the solvent to water, the (PhTe)2 compound is found more frequently in the open conformation, while 23 ACS Paragon Plus Environment


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for (PhSe)2 the distribution remains similar to that found in chloroform. This behavior, which incidentally reproduces the crystallographic finding, may be explained considering that the local solvent-solute interactions play an important role. Therefore, upon increasing the solvent polarity, this effect is emphasized, leading to different  distributions because the partial charges are neatly different for the two compounds. Finally, the computed

77

Se NMR chemical shift of (PhSe)2 in

agreement with the experimental value in chloroform is obtained from snapshots of the MD trajectory, revealing that it is mandatory to take into account the molecular flexibility in a realistic environment to reproduce this spectroscopic observable and thus gain insight on the conformational preference in solution. Ongoing work, i.e. ONIOM-based mechanistic investigation of the peroxidase activity of diphenyldichalcogenides, and, in perspective, bioincorporation of these drugs in a protein scaffold to design de novo seminatural enzymes, will provide further insight into the structure and reactivity of these dichalcogenides, in order to rationalize and support the goldmine of available experimental data related to their biomimetic anti-oxidant activity.

ASSOCIATED CONTENT Supporting information: The Supporting Information is available free of charge on the ACS Publications website at DOI: ……………. Tables with GAFF parameters, lib and frcmod files for all the studied compounds; the C++ source code and a precompiled version (linux 64 bit) of the gout2mdcrd program.


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AUTHOR INFORMATION Corresponding author: * (L.O.) E-mail: [email protected]; Phone number: +390498275140, Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This research has been funded by Università degli Studi di Padova (CPDA127392/12) and Fondazione della Cassa di Risparmio di Padova e Rovigo (Project Modeling and Monitoring Motions in ProteinsM3PC). The calculations were carried out on Eurora at CINECA (Casalecchio di Reno, Italy) thanks to two ISCRA grants (IDEAS, In silico Design of Enzymatic Antioxidant Systems, 2013, and IDEAS2, 2014, PI: Laura Orian) and on the computational facilities of Dipartimento di Scienze Chimiche (Università degli Studi di Padova). Irina Moreira was supported by FCT Investigator programmes (co-financed by European Social Fund and Programa Operacional Potencial Humano). Mr. João Martins and Mr. Amir Al Naber are acknowledged for preliminary contribution in testing the quantum chemistry level of theory employed in this work.

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(70) Allen, F. H. The Cambridge Structural Database: a quarter of a million crystal structures and raising. Acta Crys. 2002, B58, 380-388. (71) Bickelhaupt, F. M.; Solà, M.; Schleyer, P. V. R. Theoretical investigation of the relative stabilities of XSSX and X2SS isomers (X = F, Cl, H, and CH3) J. Comput. Chem. 1995, 16, 465–477. (72) Zaccaria, F.; Wolters, L. P.; Fonseca Guerra, C.; Orian, L. J. Comp. Chem. 2016 DOI: 10.1002/jcc.24383. (73) Baldo, M.; Forchioni, A.; Irgolic, K. J.; Pappalardo, G. C. Carbon-13 spin lattice relaxation and molecular motion of diphenyl dichalcogenides. J. Am. Chem. Soc. 1978, 100, 97-100. (74) Prior the use of the cc-pVTZ(-PP) basis set for Se/Te for the determination of the RESP charges, we compared the charges of (PhSe)2 calculated (i) at the usual HF/6-31G(d) level and (ii) at HF/631G(d),cc-pVTZ level, where the latter basis set has been used only for the Se atom. The relative differences of both the ESP charges and dipole moments were less than 3%. (75) To the best of our knowledge, these parameters are not available in literature. In L. Zhao, L.; Cox, A.G.; Ruzicka, J. A.; Bhat, A. A.; Zhang, W.; Taylor, E. W. PNAS 2000 97 6356–6361 the same LJ parameters of Zn, developed by S. Amirjalayer, M. Tafipolsky and R. Schmid (Angew. Chem. Int. Ed. 2007, 46, 463–466), are employed for Se, that is =2.29 Å and =0.276 Kcal mol-1, and no validation is provided. In this work, LJ  parameters for Se and Te values have been taken from UFF (Rappe, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard III, W. A.; Skiff, W. M. UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations. J. Am. Chem. Soc. 1992, 114, 10024-10035). In addition, since GAFF values show very good linear correlation with the van der Waals radii of C, H, N, O, P, S (Table S8),  values for the chalcogens were estimated accordingly. With this strategy, Se parameters turn out to be very close to those used by Zhao et al. These LJ parameters have been very recently employed by some of us for the parametrization of ff14SB of Sec and Tec. Among the preliminary results of extensive MD simulations, carried out to 34 ACS Paragon Plus Environment

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study the Se and Te based glutathione peroxidase, we observe the preservation of the catalytic pocket in which Sec/Tec are buried, and this, together with the results of the MD runs and

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chemical shift calculations included in this paper, enhances our confidence in our choice of the LJ parameters. (76) Bagno, A.; Rastrelli, F.; Saielli, G. Prediction of the 1H and 13C NMR spectra of -D-glucose in water by DFT methods and MD simulations J. Org. Chem. 2007, 72, 7373-7381. (77) Bühl, M.; Thiel, W.; Fleischer, U.; Kutzelnigg Ab initio computation of

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shifts with the IGLO-SCF, the GIAO-SCF and the GIAO-MP2 methods J. Phys. Chem. 1995, 99, 4000-4007. (78) Chesnut, D. B. Scaled DFT selenium NMR chemical shieldings Chem. Phys. 2004, 305, 237241. (79) Nakanishi, W.; Hayashi, S.; Shimizu, D.; Hada, M. Orientational effect of aryl groups on the 77

Se NMR chemical shifts: experimental and theoretical investigations Chem. Eur. J. 2006, 12, 3829-

3846.



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FOR TABLE OF CONTENTS USE ONLY


General AMBER Force Field Parameters for Diphenyl Diselenides and

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