Importance of RâCF3Â·Â·Â·O Tetrel Bonding Interactions in Biological

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On the Importance of R–CF···O Tetrel Bonding Interactions in Biological Systems Xavier Garcia-LLinas, Antonio Bauza, Saikat Kumar Seth, and Antonio Frontera J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b06052 • Publication Date (Web): 30 Jun 2017 Downloaded from http://pubs.acs.org on July 4, 2017

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The Journal of Physical Chemistry

On the Importance of R–CF3···O tetrel Bonding Interactions in Biological Systems Xavier García-LLinás‡,†, Antonio Bauzá‡,†, Saikat K. Seth§,† and Antonio Frontera†,* †

Department of Chemistry, Universitat de les Illes Balears, Crta. De Valldemossa km 7.5, 07122

Palma de Mallorca (Baleares), SPAIN §

Department of Physics, Jadavpur University, Kolkata-700032, India

Abstract

In this manuscript ab initio calculations have been combined with a search in the Protein Data Bank (PDB) to demonstrate the importance of σ-hole tetrel bonding interactions in biological systems. In particular, we focus our attention to the ability of the –CF3 group to participate in noncovalent interactions as Lewis acid and we show the importance of this interaction in the inhibition mechanism of a NADP+-dependent isocitrate dehydrogenase (IDH) enzyme that converts isocitrate to α-ketoglutarate. IDH mutations are found in multiple hematologic and solid tumors, inducing premalignant disorders. A potent triazine-based inhibitor of the mutant IDH (enasidenib) presents two –CF3 groups in the structure. One establishes a tetrel bonding interaction with an aspartate residue that contributes to the binding and selectivity of the inhibitor to the active site.

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1. Introduction The rapid development and impact of supramolecular chemistry in the scientific community is certainly related to its multidisciplinary nature.1,2 Definitely, the understanding of noncovalent forces (either weak or strong) is necessary for the chemists working in this field of research, because they are the foundation of highly specific recognition. For example, interactions between molecules with different sizes and shapes govern the creation of assemblies with high affinities even in highly competitive media.3,4,5,6 Therefore, the accurate description of noncovalent interactions between hosts and guests is crucial to succeed in this field of research. In general, strong and directional forces are commonly used for this purpose, for instance cation/anion–π,7,8 hydrogen bonding and σ-hole interactions.9,10,11,12,13,14,15,16,17,18,19 Moreover, in some cases these directional interactions are combined with very strong non-directional forces like ion pairing to be successful in highly competitive media. Since the first report of the existence of positive σ-holes on Group IV atoms by Murray et al,20 other theoretical studied have demonstrated that tetrel atoms in their sp3 hybridized form can act as Lewis acids suitable to accommodate anions/Lewis bases.21,22,23,24,25,26 Few of them are dedicated to study the smallest of the series, the carbon atom. Actually, it has recently been shown

that

strong complexes

are established

between

Lewis

bases

and

1,1,2,2-

tetracyanocyclopropane.27,28,29 Moreover, Mani and Arunan30 have explored the ability of the carbon atom in a methyl group to participate in σ-hole interactions (as a σ-hole donor, i.e. electron acceptor). They demonstrated that the smallest tetrel atom is able to act as an electrophilic center by establishing non-covalent bonds with Lewis bases (namely, noncovalent carbon bonding). Remarkably, these theoretical expectations were supported experimentally by Guru Row’s group31 by using X-ray charge density analysis. That is, experimental electron


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density topologies in an X-ray structure with the R3N+–CH3···O motif revealed a bond path connecting the oxygen atom with the –CH3 carbon atom and no other bond paths connecting the oxygen atom to the C–H hydrogen atoms were reported and revealed two distinct features of bond paths. In addition, cooperativity effects involving carbon bonding interactions, and other noncovalent interactions have been analyzed in several theoretical studies.32,33,34 Furthermore, we have recently analyzed the dual ability of the methyl group (XCH3) to act as either H-bond or carbon bond donor while interacting with oxygen atom donor groups by combining high-level ab initio calculations with the Bader’s theory of atoms in molecules. More importantly, we have demonstrated the importance of latter interactions in biological systems by examining the protein data bank (PDB).35 A rigorous statistical survey of the Cambridge structural database (CSD) together with ab initio computations has been previously reported to demonstrate that sp3 C-atom in (parasubstituted) α,α,α-trifluorotoluene has a preference for interacting with Lewis bases/anions (Y) using the small positive region in between the three F-atoms in PhCF3. This weak interaction is highly directional since the PhCF3⋯Y interaction is located in a very narrow energy-well and any distortion from linearity comes with an energy penalty. Interestingly, –CF3 groups are commonly used in medicinal chemistry to decorate enzyme inhibitors and related compounds. Thus, this non-covalent carbon bonding might turn out to be functionally relevant. Therefore, we speculated if weak non-covalent bonding with sp3 hybridized carbon involving –CF3 groups may have some relevance in ligand-protein complexes. Consequently, the aim of this paper is to conduct a rigorous search of the PDB together with ab initio computations at the RI-MP2/def2QZVP//RI-MP2/def2-TZVP level of theory on some model systems and at the RI-MP2/def2TZVP level of theory for some enzymatic models. For the present theoretical study, we


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considered the sp3 carbon atom in ArCF3 (Ar = C6F5) in several exemplifying complexes and computed their interaction energies. In addition, using the NCIplot computational tool, we characterized the tetrel bonding interaction. Finally, by using the PDB search the impact of the X–CF3···O interactions in biologically relevant protein-ligand complexes have been analyzed in detail. 2. Theoretical methods. The geometries of the complexes included in this study were computed at the RI-MP2/def2TZVP level of theory. Moreover, single point energy calculations at the RI-MP2/def2-QZVP level of theory have been also carried out. We have not taken into consideration the basis set superposition error correction since it has been reported that many times the use of counter-poise correction does not lead to improved interaction energies.36,37 This is especially relevant in postHF methods, where the application of the full counterpoise method caused a nonphysical increase in the dimension of the virtual space that produces an overestimation of the correction.38,39 In fact the extrapolations to complete basis set (CBS) are usually comparable to BSSE uncorrected energies, as recently demonstrated by Alvarez-Idaboy and Galano.40 Moreover, in an interesting manuscript reported by Dunning41 it is stated that the agreement between the uncorrected binding energies and the CBS limit ones is due to the fact that the BSSE and the basis set convergence error are often of opposite signs. As a matter of fact, the interaction energies reported herein (see Table 1) reveal that triple-ζ and quadruple-ζ calculations give almost identical results, evidencing that the BSSE is not influencing the energetic results computed with the smaller basis. The calculations have been performed by using the program TURBOMOLE version 7.0.42 The optimization of the molecular geometries has been performed imposing the Cs symmetry point group, unless otherwise noted. Frequency calculations have


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been performed at the RI-MP2/def2-TZVP level of theory and confirmed the minimum nature of the complexes. For the calculations using models of the active site of the protein, we have used the X-ray coordinates and the RI-MP2/def2-TZVP level of theory. The molecular electrostatic energy surface calculations have been performed at the MP2/6-31+G* level of theory by means of the SPARTAN software.43 The NCI plot is a visualization index based on the electron density and its derivatives, and enables identification and visualization of non-covalent interactions efficiently.44 The isosurfaces correspond to both favorable and unfavorable interactions, as differentiated by the sign of the second density Hessian eigenvalue and defined by the isosurface color. NCI analysis allows an assessment of host-guest complementarity and the extent to which weak interactions stabilize a complex. The information provided by NCI plots is essentially qualitative, i.e. which molecular regions interact. The color scheme is a red-yellow-green-blue scale with red for ρ+cut (repulsive) and blue for ρ−cut (attractive). Yellow and green surfaces correspond to weak repulsive and weak attractive interactions, respectively. 3. Results and discussion 3.1. Preliminary results First of all, we have optimized a series of donor-acceptor complexes using perfluorotoluene (PFT) as electron acceptor. The molecular electrostatic potential (MEP) surface of this compound is shown in Figure 1a. It can be observed that PFT presents an extended π-acidic surface due to the electron withdrawing nature of the substituents, thus suitable for interacting with Lewis bases/anions establishing either lone pair (lp)–π or anion–π interactions. Moreover, it also presents a small area at the sp3 C atom where the MEP is positive (σ-hole). The MEP value over the center of the ring (π–hole) is stronger (+138 kJ/mol) that that at the σ-hole (+71 kJ/mol),


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consequently it can be anticipated that π–hole complexes (anion/lp–π interactions) will present stronger binding energies than σ-hole ones (tetrel bonding). The complexes optimized in this preliminary study are shown in Figure 1b. We have used two lone pair donors and two anions as models of σ-hole acceptors that can be present in biological systems. The interaction energies are gathered in Table 1 and the geometries in Figure 2. It can be observed that the anion/lp–π complexes correspond to the global minima and exhibit strong binding energies. The tetrel bonding complexes are local minima and those involving neutral donors present modest interaction energies and long equilibrium distances. The interactions with anionic donors present significantly shorter distances and the interaction energies are more significant. It should be also emphasizing that the energies using the def2-TZVP basis set are almost identical to those using the larger def2-QZVP thus indicating that the triple-ζ is of enough quality to describe this interaction.


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Figure 1. (a) Molecular Electrostatic Potential Surface of PFT, surface at 0.002 a.u. (b) π-hole (1–4) and σ-hole (5–8) complexes studied in this work. Table 1. Interaction energies and equilibrium distances computed for complexes 1–8 at several levels of theory. Distances in Å and energies in kJ/mol. TZ’ and QZ’ stand for def2-TZVP and def2-QZVP, respectively. Complex

E (MP2/TZ’)

E (MP2/QZ’//MP2/TZ’)

Re (MP2/TZ’)

1

–21.5

–19.3

3.126

2

–25.6

–25.5

2.851

3

–91.2

–87.4

2.774

4

–76.3

–73.8

2.659

5

–3.1

–2.8

3.644

6

–3.0

–2.1

3.408

7

–11.6

–10.4

3.313

8

–8.9

–8.6

3.141


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Figure 2. RI-MP2/def2-TZVP optimized geometries of π-hole (1–4) and σ-hole (5–8) complexes studied in this work. To obtain further insight into this σ-hole tetrel bonding, the noncovalent interaction (NCI) index was computed for two representative complexes (6 and 8). As described in the literature, this approach is based on the electron density and its derivatives.44 The peaks that appear in the reduced density gradient (s) at low densities correspond to the different noncovalent interactions. The sign of the second eigenvalue (λ2) of the electron-density Hessian matrix is used to distinguish bonded (λ2 < 0) from nonbonded (λ2 > 0) interactions and its strength can be derived from the density values of the low-gradient spikes. An advantage of this method is the visualization in real space of the gradient isosurfaces. Figure 3 displays the NCI isosurfaces of complexes 6 and 8 at MP2/def2-SVP level of theory. The noncovalent interaction peaks appear at density values lower than 0.01 a.u., which corresponds to the region of weak interactions, characterized by the green color at the isosurfaces. In both complexes the isosurface area covers the carbon atom and it is also extended to the C–F bonds.

Figure 3. NCI analysis of complexes 6 and 8. The gradient isosurfaces are colored on a BGR scale according to the sign (λ2)ρ over the range −0.015 to 0.015 a.u. 3.2 PDB analysis


8

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We explored the PDB in order to find experimental support to the RCF3···O tetrel bonding interaction and also to demonstrate its importance in biologically relevant molecules. The search was carried out by means of the freely available Relibase software45 using the following criteria: (i) The –CF3 donor group belongs to the ligand and the O atom is part of the protein; (ii) C···O distance (d) is shorter than 3.35 Å (sum of vdW radii + 0.15 Å) and the X–C···O angle (A) >160°; (iii) only X-ray solid state structures were considered (no NMR resolved); and (iv) a resolution factor ≤3 Å. As a result, we found seven protein-ligand complexes exhibiting this type of bonding (see Table 2). At first sight, the number of hits seems very low, however it should be emphasized that the ligands were not designed by the original authors to have the -CF3···O interaction with the enzyme. In contrast, this interaction has been unnoticed by them, however it likely contributes to the fine-tuning the binding of the substrate to the enzyme, as further described below. The PDB codes of the seven protein-ligand complexes along with some geometric features are given in Table 2. Table 2. PDB codes, ligand IDs, O-donor amino acid and geometric features of the carbon bonding interactions. The resolution of the crystal structure is also given in Å. PDB ID

O donor amino acid

Ligand ID

distance

Angle

Resolution

3NK8

SER195

JKZ

3.28

161.2

1.15

4JA8

ASP312

1K9

3.35

164.8

1.55

4Z90

THR237

4LE

3.34

161.7

3.00

5I96

ASP312

69Q

3.21

165.1

1.55

2WM3

TYR246

NFL

3.16

174.7

1.85

3QBF

ASP30

JHG

2.96

160.4

2.35

5J7P

ASN97

6H1

2.59

163.4

1.85


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In this manuscript we use 2WM3 and 5I96 to illustrate the importance of the -CF3···O interaction in the binding of inhibitors to the active site of enzymes. The first example46 is a well resolved (resolution: 1.85 Å) crystal structure of NmrA-like family domain containing protein 1 (NMRAL1) in complex with the anti-inflammatory agent 2-[(3-trifluoromethyl)phenyl]amino-3pyridine- carboxylic acid (niflumic acid). NMRAL1 is a redox sensor protein that responses to changes in intracellular NADPH/NADP+ levels.47 The monomeric form of this protein is found at low NADPH concentrations and binds argininosuccinate synthase (ASS), the enzyme involved in nitric oxide synthesis.48 This binding inhibits ASS activity and, consequently, reduces the production of nitric oxide, thus preventing apoptosis. If the NADPH level is normal, the protein is found as a dimer and does not bind ASS.49 Interestingly, reduced levels of NMRAL1 increases nitric oxide production and reduces cell viability and, conversely, overexpression of NMRAL1 increases cell viability. The anti-inflammatory niflumic acid interacts with the protein by means of a noncovalent carbon bonding interaction (see Figure 4a) involving the CF3 group and tyrosine, among other forces. Remarkably the CF3···O distance (3.16 Å) is shorter than the sum of van der Waals radii (3.22 Å) and the interaction is very directional (A = 174.7º).


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Figure 4. (a) X-ray structure of 2WM3 with indication of the tetrel bonding interaction (distance in Å); (b) Chemical drawing of the NFL ligand; (c) NCIplot of the fragment derived from the Xray coordinates used for the calculations with indication of the TYR246 and TRP82 models. The gradient isosurfaces are colored on a BGR scale according to the sign (λ2)ρ over the range −0.015 to 0.015 a.u. We have constructed a model to energetically evaluate this interaction, where we have used TYR and some additional atoms of the peptide backbone. The model also includes a tryptophan residue that establishes a hydrogen bonding interaction with the carboxylic group of the ligand (see Figure 4c). The interaction energy is −1.25 kJ/mol that is similar to that obtained for neutral complexes 5 and 6 (see Table 1) and confirms that the interaction is very weak. Remarkably, the NCIplot shows a green isosurface between the O atom of the TYR and the carbon atom of the


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inhibitor, thus characterizing the carbon bonding interaction in 2WM3. Furthermore, it also shows a larger isosurface that characterizes the H-bonding interaction between the NFL and the TRP82 residue. The second example we selected50 corresponds to the structure of a NADP+-dependent isocitrate dehydrogenase (IDH) enzyme that converts isocitrate to α-ketoglutarate (αKG) (PDB ID: 5I96, resolution 1.55 Å. see Figure5a). IDH mutations are found in multiple hematologic and solid tumors, inducing premalignant disorders (such as myelodysplastic syndrome), and drive leukemic transformation in cooperation with other genetic events (23–25).51,52,53 In particular, mutated IDH reduces αKG to the oncometabolite (R)-2-hydroxyglutarate, that competitively inhibits α-ketoglutarate-dependent dioxygenases. In Figure 5 we represent the X-ray structure of AG-221 (a potent triazine inhibitor, also known as 69Q) complexed to the mutant IDH2 enzyme that dramatically reduces the production of the oncometabolite (IC50 = 10-20 nm). In the active site, the inhibitor is forming H-bonding interactions with two glutanamine residues (GLN316A and GLN316B). In addition, one of both CF3 groups present in the inhibitor interacts with an aspartate amino acid of the active site (ASP312). The O···CF3 distance is shorter than the sum of van der Waals radii and the directionality is the adequate for establishing a favorable interaction with the σ-hole (165.1º) of the CF3. Interestingly, it has been demonstrated that an analogous of the AG-221 inhibitor without the –CF3 groups presents a higher IC50 value (30 nm),50 suggesting that the –CF3 group is modulating the binding ability of the inhibitor, increasing the affinity for the IDH active site.


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Figure 5. (a) X-ray structure of 5I96 with indication of the carbon bonding interaction (distance in Å); (b) chemical drawing of the AG-221 inhibitor; (c) A NCIplot of the fragment (derived from the X-ray coordinates) used for the calculations with indication of the GLN316A/B and ASP312 models. The gradient isosurfaces are colored on a BGR scale according to the sign (λ2)ρ over the range −0.015 to 0.015 a.u. We have also constructed a model in this example to energetically evaluate the σ-hole interaction. We have used ASP and some additional atoms of the peptide backbone and additional formamide molecules to mimic the interaction of the inhibitor with both GLN residues (see Figure 5c). The interaction energy computed as a dimer (one monomer is AG-122 and both H-bonded formamide molecules and the other is ASP) is large (−29.6 kJ/mol) due to the anionic


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nature of the electron donor, as also observed in the anionic complexes commented above (see Table 1) and confirms that the tetrel bonding interaction is important in this example. Remarkably, the NCIplot shows a green isosurface between the O atom of the ASP and the carbon atom of the inhibitor, thus characterizing the carbon bonding interaction in 5I96. Furthermore, the NCIplot analysis also shows small isosurfaces characterizing the H-bonding interactions between the formamides and the inhibitor. Finally, it shows two small isosurfaces between a H atom of the ASP side chain and the F atoms of the –CF3 group. These C–H···F interactions likely participate in the binding mechanism and explain the larger binding energy observed in this complex compared to compounds 7 and 8. 4. Conclusions In this manuscript, we analyzed the ability of the trifluoro methyl group (XCF3) to act as σhole tetrel bond donor in complexes with Lewis bases by means of high-level ab initio calculations and the NCIplot computational tool. For X–CF3···O complexes exhibiting angles close to linearity, a carbon bonding interaction is established as confirmed by NCIplot analysis. Remarkably, we have demonstrated the importance of latter interactions in biological systems by examining the PDB and illustrated by using two selected examples with low resolution and high directionality. Since –CF3 groups are widely used to functionalize ligands used in medicinal chemistry, non-covalent carbon bonding involving this group might turn out to be as functionally relevant as other σ-hole interactions.

ASSOCIATED CONTENT Supporting Information. The Cartesian coordinates of the optimized compounds are supplied as Supporting Information


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AUTHOR INFORMATION Corresponding Author *[email protected]. Present Addresses †If an author’s address is different than the one given in the affiliation line, this information may be included here. Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. Funding Sources We thank the MINECO of Spain (project CTQ2014-57393-C2-1-P FEDER funds) for financial support. ACKNOWLEDGMENT We thank the “Centre de Tecnologies de la Informació” (CTI) at the UIB for computational facilities. S. K. Seth is grateful to the SERB-DST for Overseas Postdoctoral Fellowship (SB/OS/PDF-524/2015-16).

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