Importance of R–CF3···O Tetrel Bonding Interactions in Biological

Article pubs.acs.org/JPCA

Importance of R−CF3···O Tetrel Bonding Interactions in Biological Systems Published as part of The Journal of Physical Chemistry virtual special issue “Manuel Yanez and Otilia Mo Festschrift”. 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

§

S Supporting Information *

ABSTRACT: In this article, 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 on the ability of the −CF3 group to participate in noncovalent interactions as Lewis acids, 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.

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 noncovalent 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 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 NCIs have been analyzed in several theoretical studies.32−34 Furthermore, we have recently analyzed the dual ability of the methyl group (XCH3) to act as either a H-bond or carbon bond donor while interacting with oxygen atom donor groups by combining highlevel ab initio calculations with Bader’s theory of atoms in molecules. More importantly, we have demonstrated the importance of the 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 an sp3 C atom in

1. INTRODUCTION The rapid development and impact of supramolecular chemistry in the scientific community is certainly related to its multidisciplinary nature.1,2 Definitely, an 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.3−6 Therefore, accurate description of noncovalent interactions (NCIs) 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.9−19 Moreover, in some cases, these directional interactions are combined with very strong nondirectional 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.21−26 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.27−29 Moreover, Mani and Arunan30 have explored the ability of the carbon atom in a methyl group to participate in σ-hole © 2017 American Chemical Society

Received: June 20, 2017 Revised: June 30, 2017 Published: June 30, 2017 5371

DOI: 10.1021/acs.jpca.7b06052 J. Phys. Chem. A 2017, 121, 5371−5376

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The Journal of Physical Chemistry A (para-substituted) 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 because 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 noncovalent carbon bonding might turn out to be functionally relevant. Therefore, we speculated if weak noncovalent 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/def2-QZVP//RI-MP2/def2TZVP level of theory on some model systems and at the RIMP2/def2-TZVP level of theory for some enzymatic models. For the present theoretical study, we 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 has been analyzed in detail.

energetic results computed with the smaller basis. The calculations have been performed by using the program TURBOMOLE version 7.0.42 Optimization of the molecular geometries has been performed imposing the Cs symmetry point group, unless otherwise noted. Frequency calculations have 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 NCIs 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, that is, 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.

2. THEORETICAL METHODS The geometries of the complexes included in this study were computed at the RI-MP2/def2-TZVP level of theory. Moreover, single-point energy calculations at the RI-MP2/def2QZVP level of theory have also been carried out. We have not taken into consideration the basis set superposition error correction because it has been reported that many times the use of counterpoise correction does not lead to improved interaction energies.36,37 This is especially relevant in post-HF methods, where 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 article reported by Dunning,41 it is stated that the agreement between the uncorrected binding energies and those of the CBS limit is due to the fact that the BSSE and the basis set convergence error are often of opposite sign. 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

3. RESULTS AND DISCUSSION 3.1. Preliminary Results. First of all, we have optimized a series of donor−acceptor complexes using perfluorotoluene (PFT) as the 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

Table 1. Interaction Energies and Equilibrium Distances Computed for Complexes 1−8 at Several Levels of Theorya complex

E(MP2/TZ′)

E(MP2/QZ′//MP2/TZ′)

Re(MP2/TZ′)

1 2 3 4 5 6 7 8

−21.5 −25.6 −91.2 −76.3 −3.1 −3.0 −11.6 −8.9

−19.3 −25.5 −87.4 −73.8 −2.8 −2.1 −10.4 −8.6

3.126 2.851 2.774 2.659 3.644 3.408 3.313 3.141

Figure 1. (a) MEP surface of the PFT at 0.002 au and (b) π-hole (1− 4) and σ-hole (5−8) complexes studied in this work.

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); consequently, it can be anticipated that π-hole complexes (anion/lp−π interactions) will present stronger binding energies than σ-hole ones (tetrel

a

Distances are in Å, and energies are in kJ/mol. TZ′ and QZ′ stand for def2-TZVP and def2-QZVP, respectively. 5372

DOI: 10.1021/acs.jpca.7b06052 J. Phys. Chem. A 2017, 121, 5371−5376

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The Journal of Physical Chemistry A bonding). The complexes optimized in this preliminary study are shown in Figure 1b. We have used two lp 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

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

and the X−C···O angle (A) > 160°; (iii) only X-ray solid-state structures were considered (no NMR resolved); and (iv) there was 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; Table 2. PDB Codes, Ligand IDs, O Donor Amino Acid and Geometric Features of the Carbon Bonding Interactions, and the Resolution of the Crystal Structure, Given in Å Figure 2. RI-MP2/def2-TZVP optimized geometries of π-hole (1−4) and σ-hole (5−8) complexes studied in this work.

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 also be emphasized 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. To obtain further insight into this σ-hole tetrel bonding, the 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 NCIs. 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 lowgradient 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 the MP2/def2-SVP level of theory. The NCI peaks appear at density values lower than 0.01 au, 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. 3.2. PDB Analysis. We explored the PDB in order to find experimental support for 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) the C···O distance (d) is shorter than 3.35 Å (sum of vdW radii + 0.15 Å)

PDB ID

O donor amino acid

ligand ID

distance

angle

resolution

3NK8 4JA8 4Z90 5I96 2WM3 3QBF 5J7P

SER195 ASP312 THR237 ASP312 TYR246 ASP30 ASN97

JKZ 1K9 4LE 69Q NFL JHG 6H1

3.28 3.35 3.34 3.21 3.16 2.96 2.59

161.2 164.8 161.7 165.1 174.7 160.4 163.4

1.15 1.55 3.00 1.55 1.85 2.35 1.85

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 of 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. In this article, 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 an NmrAlike family domain containing protein 1 (NMRAL1) in the complex with the anti-inflammatory agent 2-[(3trifluoromethyl)phenyl]amino-3-pyridine- carboxylic acid (niflumic acid). NMRAL1 is a redox sensor protein that responds 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 increase nitric oxide production and reduce cell viability, and conversely, overexpression of NMRAL1 increases cell viability. The antiinflammatory 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 5373

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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 X-ray 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 of (λ2)ρ over the range of −0.015 to 0.015 au.

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) 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 of (λ2)ρ over the range of −0.015 to 0.015 au.

sum of van der Waals radii (3.22 Å), and the interaction is very directional (A = 174.7°). 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, which 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 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 that 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 Figure 5a). 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).51−53 In particular, mutated IDH reduces αKG to the oncometabolite (R)-2-hydroxyglutarate, which competitively inhibits αKG-dependent dioxygenases. In Figure 5, we represent the X-ray structure of AG-221 5374

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(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 forms 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 to establish a favorable interaction with the σ-hole (165.1°) of the CF3. Interestingly, it has been demonstrated that an analogue of the AG-221 inhibitor without the −CF3 groups presents a higher IC50 value (30 nm),50 suggesting that the −CF3 group modulates the binding ability of the inhibitor, increasing the affinity for the IDH active site. 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 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.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Antonio Frontera: 0000-0001-7840-2139 Author Contributions ‡

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. X.G.-L. and A.B. contributed equally. Funding

We thank the MINECO of Spain (Project CTQ2014-57393C2-1-P FEDER funds) for financial support. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the “Centre de Tecnologies de la Informació” (CTI) at the UIB for computational facilities. S.K.S. is grateful to the SERB-DST for an Overseas Postdoctoral Fellowship (SB/OS/ PDF-524/2015-16).

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REFERENCES

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4. CONCLUSIONS In this article, we analyzed the ability of the trifluoromethyl group (XCF3) to act as a σ-hole tetrel bond donor in complexes with Lewis bases by means of high-level ab initio calculations and the NCIplot computational tool. For X−CF 3···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 the latter interactions in biological systems by examining the PDB and illustrated this by using two selected examples with low resolution and high directionality. Because −CF3 groups are widely used to functionalize ligands used in medicinal chemistry, noncovalent carbon bonding involving this group might turn out to be as functionally relevant as other σ-hole interactions.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpca.7b06052. Cartesian coordinates of the optimized compounds (PDF) 5375

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DOI: 10.1021/acs.jpca.7b06052 J. Phys. Chem. A 2017, 121, 5371−5376